BACKGROUND Diabetic cardiomyopathy(DCM)increases the risk of hospitalization for heart failure(HF)and mortality in patients with diabetes mellitus.However,no specific therapy to delay the progression of DCM has been i...BACKGROUND Diabetic cardiomyopathy(DCM)increases the risk of hospitalization for heart failure(HF)and mortality in patients with diabetes mellitus.However,no specific therapy to delay the progression of DCM has been identified.Mitochondrial dysfunction,oxidative stress,inflammation,and calcium handling imbalance play a crucial role in the pathological processes of DCM,ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions.Empagliflozin,a novel glucoselowering agent,has been confirmed to reduce the risk of hospitalization for HF in diabetic patients.Nevertheless,the molecular mechanisms by which this agent provides cardioprotection remain unclear.AIM To investigate the effects of empagliflozin on high glucose(HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism.METHODS Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG(30 mmol/L)were separately employed as in vivo and in vitro models.Echocardiography was used to evaluate cardiac function.Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells.Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential.Furthermore,intracellular reactive oxygen species production and superoxide dismutase activity were analyzed.Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression.Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase(AMPK)and myosin phosphatase target subunit 1(MYPT1),as well as the peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α)and active caspase-3 protein levels.RESULTSIn the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin(10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis,accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease inthe phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment ofcardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis.However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG,empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylatedMYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressingPGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucosecotransporter (SGLT)2 protein expression was detected in cardiomyocytes.CONCLUSION Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HGconditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.展开更多
BACKGROUND Jiawei Jiaotai Pill is commonly used in clinical practice to reduce apoptosis,increase insulin secretion,and improve blood glucose tolerance.However,its mechanism of action in the treatment of diabetic card...BACKGROUND Jiawei Jiaotai Pill is commonly used in clinical practice to reduce apoptosis,increase insulin secretion,and improve blood glucose tolerance.However,its mechanism of action in the treatment of diabetic cardiomyopathy(DCM)remains unclear,hindering research efforts aimed at developing drugs specifically for the treatment of DCM.AIM To explore the pharmacodynamic basis and molecular mechanism of Jiawei Jiaotai Pill in DCM treatment.METHODS We explored various databases and software,including the Traditional Chinese Medicine Systems Pharmacology Database,Uniport,PubChem,GenCards,String,and Cytoscape,to identify the active components and targets of Jiawei Jiaotai Pill,and the disease targets in DCM.Protein-protein interaction network,gene ontology,and Kyoto Encyclopedia of Genes and Genomes analyses were used to determine the mechanism of action of Jiawei Jiaotai Pill in treating DCM.Molecular docking of key active components and core targets was verified using AutoDock software.RESULTS Total 42 active ingredients and 142 potential targets of Jiawei Jiaotai Pill were identified.There were 100 common targets between the DCM and Jiawei Jiaotai Pills.Through this screening process,TNF,IL6,TP53,EGFR,INS,and other important targets were identified.These targets are mainly involved in the positive regulation of the mitogen-activated protein kinase(MAPK)MAPK cascade,response to xenobiotic stimuli,response to hypoxia,positive regulation of gene expression,positive regulation of cell proliferation,negative regulation of the apoptotic process,and other biological processes.It was mainly enriched in the AGE-RAGE signaling pathway in diabetic complications,DCM,PI3K-Akt,interleukin-17,and MAPK signaling pathways.Molecular docking results showed that Jiawei Jiaotai Pill's active ingredients had good docking activity with DCM's core target.CONCLUSION The active components of Jiawei Jiaotai Pill may play a role in the treatment of DCM by reducing oxidative stress,cardiomyocyte apoptosis and fibrosis,and maintaining metabolic homeostasis.展开更多
Objective:To explore the protective effects of rhein on cardiomyocyte injury in DCM and its possible mecha-nism.Methods:The diabetic model was induced by intraperitoneal injection with streptozotocin and high-fat diet...Objective:To explore the protective effects of rhein on cardiomyocyte injury in DCM and its possible mecha-nism.Methods:The diabetic model was induced by intraperitoneal injection with streptozotocin and high-fat diet.The mice were randomly divided into control group,DM group,and DM+RH group.After 12 weeks treatment with rhein,the change of fast blood glucose,body weight,and heart weight/body weigh(t HW/BW)were observed.HE and Masson staining were used to evalu-ate myocardial structural damage.Transmission electron microscope was used to observe the myocardial mitochondrial structure.The mRNA levels of Sirt1,PGC-1α,TFAM,ANP,BNP andβ-MHC were quantified by RT-PCR.Sirt1,PGC-1α and TFAM protein levels were estimated by Western blot and IHC.Results:Compared with control group,the blood glucose,HW/BW,ANP,BNP andβ-MHC mRNA of DM group were significantly increased(P<0.05).The structures of myocardium and mitochondria were obviously destroyed in DM group.Sirt1,PGC-1α and TFAM expression were significantly decreased(P<0.05).Compared with DM group,the blood glucose,HW/BW,ANP,BNP and β-MHC mRNA of DM+RH group were decreased(P<0.05).The myocardial and mitochondrial injury were improved.Sirt1,PGC-1α and TFAM expression were significantly increased(P<0.05).Conclusion:Rhein exhibits protective effects on diabetic cardiomyopathy which may be achieved by activating Sirt1/PGC-1α pathway.展开更多
Diabetic cardiomyopathy(DCM)is commonly defined as cardiomyopathy in patients with diabetes mellitus in the absence of coronary artery disease and hypertension.As DCM is now recognized as a cause of substantial morbid...Diabetic cardiomyopathy(DCM)is commonly defined as cardiomyopathy in patients with diabetes mellitus in the absence of coronary artery disease and hypertension.As DCM is now recognized as a cause of substantial morbidity and mortality among patients with diabetes mellitus and clinical diagnosis is still inappropriate,various expert groups struggled to identify a suitable biomarker that will help in the recognition and management of DCM,with little success so far.Hence,we thought it important to address the role of biomarkers that have shown potential in either human or animal studies and which could eventually result in mitigating the poor outcomes of DCM.Among the array of biomarkers we thoroughly analyzed,long noncoding ribonucleic acids,soluble form of suppression of tumorigenicity 2 and galectin-3 seem to be most beneficial for DCM detection,as their plasma/serum levels accurately correlate with the early stages of DCM.The combination of relatively inexpensive and accurate speckle tracking echocardiography with some of the highlighted biomarkers may be a promising screening method for newly diagnosed diabetes mellitus type 2 patients.The purpose of the screening test would be to direct affected patients to more specific confirmation tests.This perspective is in concordance with current guidelines that accentuate the importance of an interdisciplinary team-based approach.展开更多
Diabetic complications,chiefly seen in long-term situations,are persistently deleterious to a large extent,requiring multi-factorial risk reduction strategies beyond glycemic control.Diabetic cardiomyopathy is one of ...Diabetic complications,chiefly seen in long-term situations,are persistently deleterious to a large extent,requiring multi-factorial risk reduction strategies beyond glycemic control.Diabetic cardiomyopathy is one of the most common deleterious diabetic complications,being the leading cause of mortality among diabetic patients.The mechanisms of diabetic cardiomyopathy are multi-factorial,involving increased oxidative stress,accumulation of advanced glycation end products(AGEs),activation of various pro-inflammatory and cell death signaling pathways,and changes in the composition of extracellular matrix with enhanced cardiac fibrosis.The novel lipid signaling system,the endocannabinoid system,has been implicated in the pathogenesis of diabetes and its complications through its two main receptors:Cannabinoid receptor type 1 and cannabinoid receptor type 2,alongside other components.However,the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated.This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy.These mechanisms include oxidative/nitrative stress,inflammation,accumulation of AGEs,cardiac remodeling,and autophagy.A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.展开更多
Diabetic cardiomyopathy is one of the life threatening complications of diabetes. A number of animal models are being used for studying diabetic cardiomyopathy. In laboratory animal models, induction of cardiomyopathy...Diabetic cardiomyopathy is one of the life threatening complications of diabetes. A number of animal models are being used for studying diabetic cardiomyopathy. In laboratory animal models, induction of cardiomyopathy happens in two stages: first being the induction of diabetic condition and the second being the induction of cardiomyopathy by prolonging diabetic condition. It takes a longer time to develop diabetes with the limited success rate for development of cardiomyopathy. Adriamycin is an effective anticancer drug limited by its major side-effect cardiomyopathy. A number of features of Adriamycin treatment mimics diabetes. We postulate that Adriamycin-induced cardiomyopathy might be used as a model system to study diabetic cardiomyopathy in rodents since a number of features of both the cardiomyopathies overlap. Left ventricular hypertrophy, systolic and diastolic dysfunction, myofibrillar loss, and fibrosis are hallmarks of both of the cardiomyopathies. At the molecular level, calcium signaling, endoplasmic reticulum stress, advance glycation endproduct activation, mitochondrial dysfunction,inflammation, lipotoxicity and oxidative stress are similar in both the cardiomyopathies.The signature profile of both the cardiomyopathies shares commonalities. In conclusion,we suggest that Adriamycin induced cardiomyopathic animal model can be used for studying diabetic cardiomyopathy and would save time for researchers working on cardiomyopathy developed in rodent using the traditional method.展开更多
Objective:To investigate the changes of serum concentration of Metrnl in diabetic cardiomyopathy mice,and the relationship between Metrnl and Diabetic cardiomyopathy(DCM)and its molecular mechanism.Methods:Fifteen mal...Objective:To investigate the changes of serum concentration of Metrnl in diabetic cardiomyopathy mice,and the relationship between Metrnl and Diabetic cardiomyopathy(DCM)and its molecular mechanism.Methods:Fifteen male mice were randomly divided into experimental group(DCM+Metrnl),model group(DCM)and control group.Metrnl concentration was measured with an enzyme-linked immunosorbent assay.The experimental group was treated with Metrnl,and the control group and model group were treated with equal volume solvent.Then the myocardial pathological changes,reactive oxygen species and the expression of PPARs and GLUT4 protein and the expression of CD36 and SOD gene were observed after 7 days of administration of recombinant Metrnl.Results:Serum Metrnl concentrations were elevated in DCM(P>0.05).Metrnl reduced the serum concentrations of total cholesterol(TG,P<0.05),triglyceride(TC,P<0.05)and low density lipoprotein cholesterol(LDL-C,P<0.05),while increased high density lipoprotein cholesterol(HDL-C,P<0.05)in DCM.In addition,Metrnl improved the energy metabolism of DCM,decreased the production of reactive oxygen species(ROS)and up-regulated the protein expressions of PPAR-a,PPAR-β/δ,GLUT4 and the expression of SOD in cardiomyocytes,while CD36 gene expression was down-regulated.Conclusion:Serum Metrnl concentrations were elevated in DCM mouse modles.Metrnl improved lipid metabolism and cardiac function in DCM.Besides,it can reduced myocardial oxidative stress injury through PPAR-β/δ,GLUT4 pathway.展开更多
Diabetic cardiomyopathy is one of the main causes of death of diabetic patients and seriously endangers human health.MiRNA is a type of endogenous non-coding RNA with a length of 18-25 nucleotides.It can regulate gene...Diabetic cardiomyopathy is one of the main causes of death of diabetic patients and seriously endangers human health.MiRNA is a type of endogenous non-coding RNA with a length of 18-25 nucleotides.It can regulate gene expression and plays an important role in the development of diabetic cardiomyopathy.This article will review the pathogenesis of diabetic cardiomyopathy and the important role of miRNA in its pathogenesis in order to provide a reference for future research.展开更多
Objective:To study the main chemical components and mechanism of Astragalus and Prunella vulgaris in the treatment of diabetes cardiomyopathy(DCM)based on network pharmacology and in vitro experiments.Methods:The main...Objective:To study the main chemical components and mechanism of Astragalus and Prunella vulgaris in the treatment of diabetes cardiomyopathy(DCM)based on network pharmacology and in vitro experiments.Methods:The main active components and prediction targets of Astragalus membranaceus and Prunella vulgaris herbal pairs were obtained by TCM Pharmacology database and analysis platform(TCMSP),and the disease genes were retrieved by genecards,OMIM,PharmGKB and drugbank databases.The disease and drug prediction targets were intersected to screen out common potential therapeutic targets.Cytoscape3.7.2 software was used to construct"drug component disease target"interaction network diagram;The PPI network of protein-protein interaction was constructed by using string database.R software was used to analyze the function enrichment of GO and KEGG for drug disease common targets,and autodock Vina 1.1.2 for molecular docking.Finally,the specific mechanism of Astragalus and Prunella vulgaris medicated serum on high glucose stimulated cardiomyocytes was verified in vitro.H9c2 cardiomyocytes were divided into five groups:normal group:low glucose(5.5 mmol/L)culture group,model group:high glucose(33 mmol/L)culture group,5%serum group:high glucose+5%Astragalus membranaceus Prunella vulgaris herb serum culture group,10%serum group:high glucose+10%Astragalus membranaceus Prunella vulgaris herb serum culture group,15%serum group:Hg high glucose+15%Astragalus membranaceus Prunella vulgaris herb serum culture group.MTT assay was used to detect the cell survival rate,and Western blot was used to detect the effect of Astragalus and Prunella vulgaris medicated serum on the expression of AKT1,p-AKT1,MAPK14 and p-MAPK14 proteins.Results:In this study,31 active components of Astragalus and Prunella vulgaris were screened,involving 157 targets of diabetes cardiomyopathy and 178 related signal pathways.The results of network analysis showed that Astragalus and Prunella vulgaris herbs may play a role in the treatment of DCM by acting on key targets such as AKT1,FOS,MAPK1,MAPK8,MAPK14,Jun and key pathways such as PI3K-AKT.Molecular docking showed that Astragalus membranaceus and Prunella vulgaris medicine had good binding between the active components luteolin,quercetin,pistil isoflavone,kaempferol and key targets such as AKT1,MAPK14,MAPK1,FOS,mapk8 and Jun,and the Vina score of luteolin and AKT1 was the lowest.The results in vitro showed that Astragalus and Prunella vulgaris medicated serum significantly improved the inhibition of H9c2 cardiomyocyte proliferation induced by high glucose,and increased the phosphorylation levels of AKT1 and MAPK14 proteins to play a role in the treatment of DCM.Conclusion:Astragalus and Prunella vulgaris have the characteristics of multi-target and multi-channel in the treatment of DCM.Its mechanism may be related to the regulation of the protein expression of p-AKT1 and p-MAPK14.These findings provide a new idea and basis for further experimental study on the mechanism of Astragalus and Prunella vulgaris in the treatment of diabetes cardiomyopathy.展开更多
Objective:To explore the potential active ingredients and targets of Astragalus,and also to predict the targets and mechanisms of Astragalus in the treatment of diabetic cardiomyopathy.Based on the predicted results,t...Objective:To explore the potential active ingredients and targets of Astragalus,and also to predict the targets and mechanisms of Astragalus in the treatment of diabetic cardiomyopathy.Based on the predicted results,the key signaling pathways were validated in a diabetic cardiomyopathy model mouse.Methods:Compounds and targets in Astragalus were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform.The protein names to corresponding"Gene Symbol ID"was convert by STRING database.We obtained targets of diabetic cardiomyopathy data from DisGeNET datasets.The protein-protein interaction network(PPI network)was established using STRING database.Cytoscape 3.6.0 was used to construct a disease-drug-target gene network map and to screen the 10 closest target genes by Cytohuba plug-in.The overlapping genes were then subjected to gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)-based enrichment analysis.Finally,the key molecules of the MAPK signaling pathway were validated by in vitro experiments.Animal experiments were performed using 21 Kunming mice randomly divided into normal group,model group,and Chinese herbal medicine Astragalus group,with seven mice in each group.The myocardium of mice in each group was stained with HE to compare the pathological morphological changes,and Western Blot was also used to compare the key molecules of MAPK signaling pathway,ERK1 and p-p38.Results:Astragalus contained 20 active ingredients with 188 corresponding targets,220 targets related to diabetic cardiomyopathy and 37 targets acting in conjunction with Astragalus.The common targets were imported into the STRING database to obtain a PPI network graph of overlapping genes,with 37 nodes and 391 edges.The PPI network map was imported into Cytoscape 3.6.0 software,and the most significant top 10 hub genes were obtained using the MCC algorithm in the cytoHubba plugin,namely AKT1,TP53,CASP3,MMP9,EGF,IL-10,CXCL8,IL-1β,VEGFA,PPARG.GO functional enrichment analysis yielded 40 entries for biological process(BP),23 entries for cellular component(CC),22 entries for molecular function(MF)and 94 entries for KEGG pathway enrichment screening,mainly involving PI3K-AKT,MAPK,HIF-1,FOXO,TNP pathway and other inflammation or apoptosis regulatory pathways.Animal experiments showed that Astragalus can improve the inflammatory state of myocardial tissue in mice with diabetic cardiomyopathy,and the expression of ERK1 and p-p38 protein in myocardial tissue of mice in the model group was higher than that in the normal group(P<0.05,P<0.01),and after the intervention with Astragalus,the expression of ERK1 and p-p38 protein was significantly lower than that in the model group,and the difference was statistically significant(P<0.05,P<0.01).Conclusion:Astragalus has multi-target,multi-component and multi-pathway action characteristics in the treatment of diabetic cardiomyopathy,which can exert anti-inflammatory and anti-oxidative stress effects by regulating protein expression of MAPK signaling pathway ERK1,p-p38.展开更多
Objectives It is not fully clarified how diabetes mellitus induced cardiac dysfunction and myocardial ultrastructural changes in the early state.In the present study,we provided an integrated approach to investigate e...Objectives It is not fully clarified how diabetes mellitus induced cardiac dysfunction and myocardial ultrastructural changes in the early state.In the present study,we provided an integrated approach to investigate early changes in myocardial function of diabetic rabbits and assessed the structural alteration.Methods and Results Diabetes was induced by alloxan injection.After 30 days,echocardio- graphy and left ventricular cannulation were performed in dia- betic(D,n=8) and control rabbits(C,n= 10).After catheterization, animals were killed for histological studies.Hema-toxylin -eosin and Masson’s Trichrome staining of the heart were analyzed.The ultrastructure of left ventricle was also examined with electron microscopy.Echocardiography revealed that early diabetic cardiomyopathy had impaired LV diastolic function expressed by diminished E-waves,increased Awaves, E/A ratio reversion and increased E-wave deceleration time(EDT).Concurrently,LV end-diastolic pressure(LVEDP) and diastolic time constant(T) were increased,minimum dP/ dt(LV-dp/dt)was reduced,obtained through cardiac catheterization.There were no significant differences in LV ejection fraction(EF),LV peak systolic pressure(LVSP), or maximum dP/dt(LV + dp/dt).Qualitative light microscopy revealed no histologic changes in myocardium from diabetic rabbits.The most evident ultrastructural change was spotted myofibrillar damage,while interstitial fibrosis was slight.Conclusions These results suggest that early diabetic cardiomyopathy in animal model is characterized by left ventricular diastolic dysfunction,both impaired active relaxation and increased passive chamber stiffness.Whereas,left ventricular systolic function can remain normal.It might partly contribute to myofibrillar damage,but not myocardial fibrosis.展开更多
Diabetic cardiomyopathy(DCM)is a metabolic disease and a leading cause of heart failure among people with diabetes.Mass spectrometry imaging(MSI)is a versatile technique capable of combining the molecular specificity ...Diabetic cardiomyopathy(DCM)is a metabolic disease and a leading cause of heart failure among people with diabetes.Mass spectrometry imaging(MSI)is a versatile technique capable of combining the molecular specificity of mass spectrometry(MS)with the spatial information of imaging.In this study,we used MSI to visualize metabolites in the rat heart with high spatial resolution and sensitivity.We optimized the air flow-assisted desorption electrospray ionization(AFADESI)-MSI platform to detect a wide range of metabolites,and then used matrix-assisted laser desorption ionization(MALDI)-MSI for increasing metabolic coverage and improving localization resolution.AFADESI-MSI detected 214 and 149 metabolites in positive and negative analyses of rat heart sections,respectively,while MALDI-MSI detected 61 metabolites in negative analysis.Our study revealed the heterogenous metabolic profile of the heart in a DCM model,with over 105 region-specific changes in the levels of a wide range of metabolite classes,including carbohydrates,amino acids,nucleotides,and their derivatives,fatty acids,glycerol phospholipids,carnitines,and metal ions.The repeated oral administration of ferulic acid during 20 weeks significantly improved most of the metabolic disorders in the DCM model.Our findings provide novel insights into the molecular mechanisms underlying DCM and the potential of ferulic acid as a therapeutic agent for treating this condition.展开更多
BACKGROUND Diabetic cardiomyopathy(DCM),which is a complication of diabetes,poses a great threat to public health.Recent studies have confirmed the role of NLRP3(NOD-like receptor protein 3)activation in DCM developme...BACKGROUND Diabetic cardiomyopathy(DCM),which is a complication of diabetes,poses a great threat to public health.Recent studies have confirmed the role of NLRP3(NOD-like receptor protein 3)activation in DCM development through the inflammatory response.Teneligliptin is an oral hypoglycemic dipeptidyl peptidase-IV inhibitor used to treat diabetes.Teneligliptin has recently been reported to have anti-inflammatory and protective effects on myocardial cells.AIM To examine the therapeutic effects of teneligliptin on DCM in diabetic mice.METHODS Streptozotocin was administered to induce diabetes in mice,followed by treatment with 30 mg/kg teneligliptin.RESULTS Marked increases in cardiomyocyte area and cardiac hypertrophy indicator heart weight/tibia length reductions in fractional shortening,ejection fraction,and heart rate;increases in creatine kinase-MB(CK-MB),aspartate transaminase(AST),and lactate dehydrogenase(LDH)levels;and upregulated NADPH oxidase 4 were observed in diabetic mice,all of which were significantly reversed by teneligliptin.Moreover,NLRP3 inflammasome activation and increased release of interleukin-1βin diabetic mice were inhibited by teneligliptin.Primary mouse cardiomyocytes were treated with high glucose(30 mmol/L)with or without teneligliptin(2.5 or 5μM)for 24 h.NLRP3 inflammasome activation.Increases in CKMB,AST,and LDH levels in glucose-stimulated cardiomyocytes were markedly inhibited by teneligliptin,and AMP(p-adenosine 5‘-monophosphate)-p-AMPK(activated protein kinase)levels were increased.Furthermore,the beneficial effects of teneligliptin on hyperglycaemia-induced cardiomyocytes were abolished by the AMPK signaling inhibitor compound C.CONCLUSION Overall,teneligliptin mitigated DCM by mitigating activation of the NLRP3 inflammasome.展开更多
Objective Diabetic cardiomyopathy(DCM)represents a substantial risk factor for heart failure and increased mortality in individuals afflicted with diabetes mellitus(DM).DCM typically manifests as myocardial fibrosis,m...Objective Diabetic cardiomyopathy(DCM)represents a substantial risk factor for heart failure and increased mortality in individuals afflicted with diabetes mellitus(DM).DCM typically manifests as myocardial fibrosis,myocardial hypertrophy,and impaired left ventricular diastolic function.While the clinical utility of the Jianpi Qinghua(JPQH)formula has been established in treating diabetes and insulin resistance,its potential efficacy in alleviating diabetic cardiomyopathy remains uncertain.This study aims to investigate the impact and underlying molecular mechanisms of the JPQH formula(JPQHF)in ameliorating myocardial injury in nonobese diabetic rats,specifically focusing on apoptosis and inflammation.Methods Wistar rats were assigned as the normal control group(CON),while Goto-Kakizaki(GK)rats were randomly divided into three groups:DM,DM treated with the JPQHF,and DM treated with metformin(MET).Following a 4-week treatment regimen,various biochemical markers related to glucose metabolism,cardiac function,cardiac morphology,and myocardial ultrastructure in GK rats were assessed.RNA sequencing was utilized to analyze differential gene expression and identify potential therapeutic targets.In vitro experiments involved high glucose to induce apoptosis and inflammation in H9c2 cells.Cell viability was evaluated using CCK-8 assay,apoptosis was monitored via flow cytometry,and the production of inflammatory cytokines was measured using quantitative real-time PCR(qPCR)and ELISA.Protein expression levels were determined by Western blotting analysis.The investigation also incorporated the use of MAPK inhibitors to further elucidate the mechanism at both the transcriptional and protein levels.Results The JPQHF group exhibited significant reductions in interventricular septal thickness at end-systole(IVSs)and left ventricular internal diameter at end-systole and end-diastole(LVIDs and LVIDd).JPQHF effectively suppressed high glucose-induced activation of IL-1βand caspase 3 in cardiomyocytes.Furthermore,JPQHF downregulated the expression of myocardial JunB/c-Fos,which was upregulated in both diabetic rats and high glucose-treated H9c2 cells.Conclusion The JPQH formula holds promise in mitigating diabetic myocardial apoptosis and inflammation in cardiomyocytes by inhibiting JunB/c-Fos expression through suppressing the MAPK(p38 and ERK1/2)pathway.展开更多
OBJECTIVE:To examine the protective effect of ginsenoside Rb1(Rb1),the main component of Renshen(Radix Ginseng),on cardiomyopathy in db/db mice exposed to chronic intermittent hypoxia(CIH)and explore the potential und...OBJECTIVE:To examine the protective effect of ginsenoside Rb1(Rb1),the main component of Renshen(Radix Ginseng),on cardiomyopathy in db/db mice exposed to chronic intermittent hypoxia(CIH)and explore the potential underlying mechanism of Rb1 in treating diabetic cardiomyopathy(DCM).METHODS:The db/db mice were randomly separated into five groups:normal control group,model group,Rb120 mg/kg group,Rb140 mg/kg group,and glucagon-like peptide-1(GLP-1)group.Mice were exposed to aircondition or CIH for 8 weeks,and Rb1 and GLP-1 were administrated before CIH exposure every day.Oral glucose tolerance test(OGTT),intraperitoneal insulin tolerance test(IPITT),total cholesterol(TC),triglyceride(TG),and high-density lipoprotein cholesterol(HDL-C)were detected to evaluate glycolipid metabolism.The level of insulin was detected by a mouse enzyme-linked immunosorbent assay(ELISA).Cardiac function was detected by echocardiography,and myocardial pathology was observed by hematoxylin-eosin and Masson staining.The expression of collagenⅠand collagenⅢwas detected by immunohistochemistry.Adenosine monophosphate-activated protein kinase(AMPK)/Nrf2/heme oxygenase-1(HO-1)signaling pathway was detected by Western blot and immunofluorescence.RESULTS:Rb1 treatment could improve glucose tolerance and the level of cardiac function indexes,and inhibit the level of oxidative stress indexes and the expression of collagenⅠand collagenⅢ.Moreover,Rb1 treatment enhanced AMPK phosphorylation and increased Nrf2 and HO-1 expression.CONCLUSION:Rb1 treatment alleviated CIH-induced diabetic cardiomyopathy and glycolipid metabolism disorders in db/db mice by inhibiting oxidative stress and regulating the AMPK/Nrf2/HO-1 signaling pathway.展开更多
Herein,we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy(DCM)by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model.Advanced glycation ...Herein,we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy(DCM)by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model.Advanced glycation end-products(AGEs),an important pathogenic factor of DCM,were found to induce ferroptosis in engineered cardiac tissues(ECTs),as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7 A11 levels.Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy.Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction.Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM.Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes.Nuclear factor erythroid 2-related factor 2(NRF2)activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7 A11 levels.The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase(AMPK)-dependent.These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM;sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation.This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.展开更多
Diabetic cardiomyopathy(DCM)is a common complication in diabetic patients.The molecular mechanisms of DCM remain to be fully elucidated.The intronic long noncoding RNA of DACH1(lnc DACH1)has been demonstrated to be cl...Diabetic cardiomyopathy(DCM)is a common complication in diabetic patients.The molecular mechanisms of DCM remain to be fully elucidated.The intronic long noncoding RNA of DACH1(lnc DACH1)has been demonstrated to be closely associated with heart failure and cardiac regeneration.In this study,we investigated the role of lnc DACH1 in DCM and the underlying molecular mechanisms.The expression of lnc DACH1 was increased in DCM hearts and in high glucose-treated cardiomyocytes.Knockout of lnc DACH1 reduced mitochondrial oxidative stress,cell apoptosis,cardiac fibrosis and hypertrophy,and improved cardiac function in DCM mice.Overexpression of lnc DACH1 exacerbated mitochondria-derived reactive oxygen species(ROS)level and apoptosis,decreased activity of manganese superoxide dismutase(Mn-SOD);while silencing of lnc DACH1 attenuated ROS production,mitochondrial dysfunction,cell apoptosis,and increased the activity of Mn-SOD in cardiomyocytes treated with high glucose.Lnc DACH1 directly bound to sirtuin3(SIRT3)and facilitated its degradation by ubiquitination,therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts.In addition,SIRT3 silencing abrogated the protective effects of lnc DACH1 deficiency in cardiomyocytes.In summary,lnc DACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated SIRT3 degradation in mouse hearts.Inhibition of lnc DACH1 represents a novel therapeutic strategy for the intervention of diabetic cardiomyopathy.展开更多
Cardiovascular diseases account for approximately 80%of deaths among individuals with diabetes mellitus,with diabetic cardiomyopathy as the major diabetic cardiovascular complication.Hyperglycemia is a symptom that ab...Cardiovascular diseases account for approximately 80%of deaths among individuals with diabetes mellitus,with diabetic cardiomyopathy as the major diabetic cardiovascular complication.Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy,fibrosis,apoptosis,and other pathophysiological changes.Although glycemic control has long been at the center of diabetes therapy,multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes.This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level.This process is now referred to as hyperglycemic memory(HGM)phenomenon.We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.展开更多
Diabetic cardiomyopathy(DCM)is currently a progressive and nonstoppable complication in type 2 diabetic patients.Metabolic insults and insulin resistance are involved in its pathogenesis;however,the underlying mechani...Diabetic cardiomyopathy(DCM)is currently a progressive and nonstoppable complication in type 2 diabetic patients.Metabolic insults and insulin resistance are involved in its pathogenesis;however,the underlying mechanisms are still not clearly understood.Here we show that calcium dysregulation can be both a cause and a consequence of cardiac insulin resistance that leads to DCM.A western diet induces the development of DCM through at least three phases in mice,among which an early phase depends on impaired Thr^(484)-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a(SERCA2a)elicited by insulin resistance.Mutation of SERCA2a-Thr^(484) to a nonphosphorylatable alanine delays calcium re-uptake into the sarcoplasmic reticulum in the cardiomyocytes and decreases cardiac function at the baseline.Importantly,this mutation blunts the early phase of DCM,but has no effect on disease progression in the following phases.Interestingly,impairment of sarcoplasmic reticulum calcium re-uptake caused by the SERCA2a-Thr^(484) mutation inhibited processing of insulin receptor precursor through FURIN convertase,resulting in cardiac insulin resistance.Collectively,these data reveal a bidirectional relationship between insulin resistance and impairment of calcium homeostasis,which may underlie the early pathogenesis of DCM.Our findings have therapeutic implications for early intervention of DCM.展开更多
Myocardial fibrosis is an important manifestation of diabetic cardiomyopathy.This study investigated the potential mechanism of diabetic myocardial fibrosis.Male C57BL/6J and db/db mice aged 8 weeks were randomly divi...Myocardial fibrosis is an important manifestation of diabetic cardiomyopathy.This study investigated the potential mechanism of diabetic myocardial fibrosis.Male C57BL/6J and db/db mice aged 8 weeks were randomly divided into the diabetic(DB)and control groups.At 20 weeks,the mouse heart was harvested and subjected to hematoxylin-eosin staining(HE)and Masson staining to investigate the degree of fibrosis.The expressions of transforming growth factor-beta 1(TGF-β1),collagen-III,B-cell lymphoma-2(Bcl2),Bcl2-associated X protein(Bax),cleaved gasdermin D(GSDMD),cysteinyl aspartate specific proteinase-1(caspase-1),apoptosis-associated speck-like protein containing a CARD(ASC),and nucleotide-binding oligomerization domain(NOD)-like receptor 3(NLRP3)were measured by western blotting.Immunohistochemistry and TdT-mediated dUTP nick end labeling(TUNEL)staining were performed to analyze the development of apoptosis and pyroptosis.A significant increase in body weight and blood glucose in the DB group was observed.Myocardial pathological injury,fibrosis,apoptosis,and pyroptosis were more obvious and serious in the DB group.The expression of anti-apoptotic Bcl2 significantly decreased,while the expression levels of pro-apoptotic Bax,caspase-3,and pyroptosis-related proteins,such as cleaved GSDMD,and caspase-1 in the DB group were significantly increased.Pyroptosis and apoptosis were probably the main mechanisms that caused myocardial fibrosis in mice with diabetes.展开更多
基金Health Commission of Hebei Province,No.20210196S&T Program of Hebei,No.22377726D。
文摘BACKGROUND Diabetic cardiomyopathy(DCM)increases the risk of hospitalization for heart failure(HF)and mortality in patients with diabetes mellitus.However,no specific therapy to delay the progression of DCM has been identified.Mitochondrial dysfunction,oxidative stress,inflammation,and calcium handling imbalance play a crucial role in the pathological processes of DCM,ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions.Empagliflozin,a novel glucoselowering agent,has been confirmed to reduce the risk of hospitalization for HF in diabetic patients.Nevertheless,the molecular mechanisms by which this agent provides cardioprotection remain unclear.AIM To investigate the effects of empagliflozin on high glucose(HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism.METHODS Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG(30 mmol/L)were separately employed as in vivo and in vitro models.Echocardiography was used to evaluate cardiac function.Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells.Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential.Furthermore,intracellular reactive oxygen species production and superoxide dismutase activity were analyzed.Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression.Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase(AMPK)and myosin phosphatase target subunit 1(MYPT1),as well as the peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α)and active caspase-3 protein levels.RESULTSIn the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin(10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis,accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease inthe phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment ofcardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis.However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG,empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylatedMYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressingPGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucosecotransporter (SGLT)2 protein expression was detected in cardiomyocytes.CONCLUSION Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HGconditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.
基金Supported by Natural Science Basic Research Plan in the Shaanxi Province of China,No.2021JM-549,The Plan Project of Shaanxi Provincial Administration of Traditional Chinese Medicine,No.2021-ZZ-JC011The Second Youth Science and Technology Talents Project of Shaanxi Provincial Administration of Traditional Chinese Medicine,No.2023-ZQNY-017.
文摘BACKGROUND Jiawei Jiaotai Pill is commonly used in clinical practice to reduce apoptosis,increase insulin secretion,and improve blood glucose tolerance.However,its mechanism of action in the treatment of diabetic cardiomyopathy(DCM)remains unclear,hindering research efforts aimed at developing drugs specifically for the treatment of DCM.AIM To explore the pharmacodynamic basis and molecular mechanism of Jiawei Jiaotai Pill in DCM treatment.METHODS We explored various databases and software,including the Traditional Chinese Medicine Systems Pharmacology Database,Uniport,PubChem,GenCards,String,and Cytoscape,to identify the active components and targets of Jiawei Jiaotai Pill,and the disease targets in DCM.Protein-protein interaction network,gene ontology,and Kyoto Encyclopedia of Genes and Genomes analyses were used to determine the mechanism of action of Jiawei Jiaotai Pill in treating DCM.Molecular docking of key active components and core targets was verified using AutoDock software.RESULTS Total 42 active ingredients and 142 potential targets of Jiawei Jiaotai Pill were identified.There were 100 common targets between the DCM and Jiawei Jiaotai Pills.Through this screening process,TNF,IL6,TP53,EGFR,INS,and other important targets were identified.These targets are mainly involved in the positive regulation of the mitogen-activated protein kinase(MAPK)MAPK cascade,response to xenobiotic stimuli,response to hypoxia,positive regulation of gene expression,positive regulation of cell proliferation,negative regulation of the apoptotic process,and other biological processes.It was mainly enriched in the AGE-RAGE signaling pathway in diabetic complications,DCM,PI3K-Akt,interleukin-17,and MAPK signaling pathways.Molecular docking results showed that Jiawei Jiaotai Pill's active ingredients had good docking activity with DCM's core target.CONCLUSION The active components of Jiawei Jiaotai Pill may play a role in the treatment of DCM by reducing oxidative stress,cardiomyocyte apoptosis and fibrosis,and maintaining metabolic homeostasis.
基金National Natural Science Foundation Project (No.81873174)。
文摘Objective:To explore the protective effects of rhein on cardiomyocyte injury in DCM and its possible mecha-nism.Methods:The diabetic model was induced by intraperitoneal injection with streptozotocin and high-fat diet.The mice were randomly divided into control group,DM group,and DM+RH group.After 12 weeks treatment with rhein,the change of fast blood glucose,body weight,and heart weight/body weigh(t HW/BW)were observed.HE and Masson staining were used to evalu-ate myocardial structural damage.Transmission electron microscope was used to observe the myocardial mitochondrial structure.The mRNA levels of Sirt1,PGC-1α,TFAM,ANP,BNP andβ-MHC were quantified by RT-PCR.Sirt1,PGC-1α and TFAM protein levels were estimated by Western blot and IHC.Results:Compared with control group,the blood glucose,HW/BW,ANP,BNP andβ-MHC mRNA of DM group were significantly increased(P<0.05).The structures of myocardium and mitochondria were obviously destroyed in DM group.Sirt1,PGC-1α and TFAM expression were significantly decreased(P<0.05).Compared with DM group,the blood glucose,HW/BW,ANP,BNP and β-MHC mRNA of DM+RH group were decreased(P<0.05).The myocardial and mitochondrial injury were improved.Sirt1,PGC-1α and TFAM expression were significantly increased(P<0.05).Conclusion:Rhein exhibits protective effects on diabetic cardiomyopathy which may be achieved by activating Sirt1/PGC-1α pathway.
文摘Diabetic cardiomyopathy(DCM)is commonly defined as cardiomyopathy in patients with diabetes mellitus in the absence of coronary artery disease and hypertension.As DCM is now recognized as a cause of substantial morbidity and mortality among patients with diabetes mellitus and clinical diagnosis is still inappropriate,various expert groups struggled to identify a suitable biomarker that will help in the recognition and management of DCM,with little success so far.Hence,we thought it important to address the role of biomarkers that have shown potential in either human or animal studies and which could eventually result in mitigating the poor outcomes of DCM.Among the array of biomarkers we thoroughly analyzed,long noncoding ribonucleic acids,soluble form of suppression of tumorigenicity 2 and galectin-3 seem to be most beneficial for DCM detection,as their plasma/serum levels accurately correlate with the early stages of DCM.The combination of relatively inexpensive and accurate speckle tracking echocardiography with some of the highlighted biomarkers may be a promising screening method for newly diagnosed diabetes mellitus type 2 patients.The purpose of the screening test would be to direct affected patients to more specific confirmation tests.This perspective is in concordance with current guidelines that accentuate the importance of an interdisciplinary team-based approach.
文摘Diabetic complications,chiefly seen in long-term situations,are persistently deleterious to a large extent,requiring multi-factorial risk reduction strategies beyond glycemic control.Diabetic cardiomyopathy is one of the most common deleterious diabetic complications,being the leading cause of mortality among diabetic patients.The mechanisms of diabetic cardiomyopathy are multi-factorial,involving increased oxidative stress,accumulation of advanced glycation end products(AGEs),activation of various pro-inflammatory and cell death signaling pathways,and changes in the composition of extracellular matrix with enhanced cardiac fibrosis.The novel lipid signaling system,the endocannabinoid system,has been implicated in the pathogenesis of diabetes and its complications through its two main receptors:Cannabinoid receptor type 1 and cannabinoid receptor type 2,alongside other components.However,the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated.This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy.These mechanisms include oxidative/nitrative stress,inflammation,accumulation of AGEs,cardiac remodeling,and autophagy.A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
基金financially supported by the Department of Science and Technology and Science and Engineering Research Board,New Delhi through the provided grant-in aid(Grant number:SB/YS/LS-99/2013)
文摘Diabetic cardiomyopathy is one of the life threatening complications of diabetes. A number of animal models are being used for studying diabetic cardiomyopathy. In laboratory animal models, induction of cardiomyopathy happens in two stages: first being the induction of diabetic condition and the second being the induction of cardiomyopathy by prolonging diabetic condition. It takes a longer time to develop diabetes with the limited success rate for development of cardiomyopathy. Adriamycin is an effective anticancer drug limited by its major side-effect cardiomyopathy. A number of features of Adriamycin treatment mimics diabetes. We postulate that Adriamycin-induced cardiomyopathy might be used as a model system to study diabetic cardiomyopathy in rodents since a number of features of both the cardiomyopathies overlap. Left ventricular hypertrophy, systolic and diastolic dysfunction, myofibrillar loss, and fibrosis are hallmarks of both of the cardiomyopathies. At the molecular level, calcium signaling, endoplasmic reticulum stress, advance glycation endproduct activation, mitochondrial dysfunction,inflammation, lipotoxicity and oxidative stress are similar in both the cardiomyopathies.The signature profile of both the cardiomyopathies shares commonalities. In conclusion,we suggest that Adriamycin induced cardiomyopathic animal model can be used for studying diabetic cardiomyopathy and would save time for researchers working on cardiomyopathy developed in rodent using the traditional method.
基金Fund Project:Scientific Research Fund Project of Science and Technology Department of Sichuan Province(grant number(No.[2012]62012JY0068))Science Foundation of the Sichuan Medical Association Shihuida Project(No.2016SHD012)the Doctoral Research Foundation of the Affiliated Hospital of Southwest Medical University(No.2018099)。
文摘Objective:To investigate the changes of serum concentration of Metrnl in diabetic cardiomyopathy mice,and the relationship between Metrnl and Diabetic cardiomyopathy(DCM)and its molecular mechanism.Methods:Fifteen male mice were randomly divided into experimental group(DCM+Metrnl),model group(DCM)and control group.Metrnl concentration was measured with an enzyme-linked immunosorbent assay.The experimental group was treated with Metrnl,and the control group and model group were treated with equal volume solvent.Then the myocardial pathological changes,reactive oxygen species and the expression of PPARs and GLUT4 protein and the expression of CD36 and SOD gene were observed after 7 days of administration of recombinant Metrnl.Results:Serum Metrnl concentrations were elevated in DCM(P>0.05).Metrnl reduced the serum concentrations of total cholesterol(TG,P<0.05),triglyceride(TC,P<0.05)and low density lipoprotein cholesterol(LDL-C,P<0.05),while increased high density lipoprotein cholesterol(HDL-C,P<0.05)in DCM.In addition,Metrnl improved the energy metabolism of DCM,decreased the production of reactive oxygen species(ROS)and up-regulated the protein expressions of PPAR-a,PPAR-β/δ,GLUT4 and the expression of SOD in cardiomyocytes,while CD36 gene expression was down-regulated.Conclusion:Serum Metrnl concentrations were elevated in DCM mouse modles.Metrnl improved lipid metabolism and cardiac function in DCM.Besides,it can reduced myocardial oxidative stress injury through PPAR-β/δ,GLUT4 pathway.
基金National natural science foundation of China(No.81774254)
文摘Diabetic cardiomyopathy is one of the main causes of death of diabetic patients and seriously endangers human health.MiRNA is a type of endogenous non-coding RNA with a length of 18-25 nucleotides.It can regulate gene expression and plays an important role in the development of diabetic cardiomyopathy.This article will review the pathogenesis of diabetic cardiomyopathy and the important role of miRNA in its pathogenesis in order to provide a reference for future research.
基金National Natural Science Foundation of China(No.81974541)。
文摘Objective:To study the main chemical components and mechanism of Astragalus and Prunella vulgaris in the treatment of diabetes cardiomyopathy(DCM)based on network pharmacology and in vitro experiments.Methods:The main active components and prediction targets of Astragalus membranaceus and Prunella vulgaris herbal pairs were obtained by TCM Pharmacology database and analysis platform(TCMSP),and the disease genes were retrieved by genecards,OMIM,PharmGKB and drugbank databases.The disease and drug prediction targets were intersected to screen out common potential therapeutic targets.Cytoscape3.7.2 software was used to construct"drug component disease target"interaction network diagram;The PPI network of protein-protein interaction was constructed by using string database.R software was used to analyze the function enrichment of GO and KEGG for drug disease common targets,and autodock Vina 1.1.2 for molecular docking.Finally,the specific mechanism of Astragalus and Prunella vulgaris medicated serum on high glucose stimulated cardiomyocytes was verified in vitro.H9c2 cardiomyocytes were divided into five groups:normal group:low glucose(5.5 mmol/L)culture group,model group:high glucose(33 mmol/L)culture group,5%serum group:high glucose+5%Astragalus membranaceus Prunella vulgaris herb serum culture group,10%serum group:high glucose+10%Astragalus membranaceus Prunella vulgaris herb serum culture group,15%serum group:Hg high glucose+15%Astragalus membranaceus Prunella vulgaris herb serum culture group.MTT assay was used to detect the cell survival rate,and Western blot was used to detect the effect of Astragalus and Prunella vulgaris medicated serum on the expression of AKT1,p-AKT1,MAPK14 and p-MAPK14 proteins.Results:In this study,31 active components of Astragalus and Prunella vulgaris were screened,involving 157 targets of diabetes cardiomyopathy and 178 related signal pathways.The results of network analysis showed that Astragalus and Prunella vulgaris herbs may play a role in the treatment of DCM by acting on key targets such as AKT1,FOS,MAPK1,MAPK8,MAPK14,Jun and key pathways such as PI3K-AKT.Molecular docking showed that Astragalus membranaceus and Prunella vulgaris medicine had good binding between the active components luteolin,quercetin,pistil isoflavone,kaempferol and key targets such as AKT1,MAPK14,MAPK1,FOS,mapk8 and Jun,and the Vina score of luteolin and AKT1 was the lowest.The results in vitro showed that Astragalus and Prunella vulgaris medicated serum significantly improved the inhibition of H9c2 cardiomyocyte proliferation induced by high glucose,and increased the phosphorylation levels of AKT1 and MAPK14 proteins to play a role in the treatment of DCM.Conclusion:Astragalus and Prunella vulgaris have the characteristics of multi-target and multi-channel in the treatment of DCM.Its mechanism may be related to the regulation of the protein expression of p-AKT1 and p-MAPK14.These findings provide a new idea and basis for further experimental study on the mechanism of Astragalus and Prunella vulgaris in the treatment of diabetes cardiomyopathy.
基金Hainan Provincial Natural Science Foundation Innovation Research Team Project(No.2019CXTD407)Hainan Medical College Youth Cultivation Fund Project(No.HYPY201912)The Youth Cultivation Fund of the First Affiliated Hospital of Hainan Medical College(No.HYYFYPY202006)。
文摘Objective:To explore the potential active ingredients and targets of Astragalus,and also to predict the targets and mechanisms of Astragalus in the treatment of diabetic cardiomyopathy.Based on the predicted results,the key signaling pathways were validated in a diabetic cardiomyopathy model mouse.Methods:Compounds and targets in Astragalus were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform.The protein names to corresponding"Gene Symbol ID"was convert by STRING database.We obtained targets of diabetic cardiomyopathy data from DisGeNET datasets.The protein-protein interaction network(PPI network)was established using STRING database.Cytoscape 3.6.0 was used to construct a disease-drug-target gene network map and to screen the 10 closest target genes by Cytohuba plug-in.The overlapping genes were then subjected to gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)-based enrichment analysis.Finally,the key molecules of the MAPK signaling pathway were validated by in vitro experiments.Animal experiments were performed using 21 Kunming mice randomly divided into normal group,model group,and Chinese herbal medicine Astragalus group,with seven mice in each group.The myocardium of mice in each group was stained with HE to compare the pathological morphological changes,and Western Blot was also used to compare the key molecules of MAPK signaling pathway,ERK1 and p-p38.Results:Astragalus contained 20 active ingredients with 188 corresponding targets,220 targets related to diabetic cardiomyopathy and 37 targets acting in conjunction with Astragalus.The common targets were imported into the STRING database to obtain a PPI network graph of overlapping genes,with 37 nodes and 391 edges.The PPI network map was imported into Cytoscape 3.6.0 software,and the most significant top 10 hub genes were obtained using the MCC algorithm in the cytoHubba plugin,namely AKT1,TP53,CASP3,MMP9,EGF,IL-10,CXCL8,IL-1β,VEGFA,PPARG.GO functional enrichment analysis yielded 40 entries for biological process(BP),23 entries for cellular component(CC),22 entries for molecular function(MF)and 94 entries for KEGG pathway enrichment screening,mainly involving PI3K-AKT,MAPK,HIF-1,FOXO,TNP pathway and other inflammation or apoptosis regulatory pathways.Animal experiments showed that Astragalus can improve the inflammatory state of myocardial tissue in mice with diabetic cardiomyopathy,and the expression of ERK1 and p-p38 protein in myocardial tissue of mice in the model group was higher than that in the normal group(P<0.05,P<0.01),and after the intervention with Astragalus,the expression of ERK1 and p-p38 protein was significantly lower than that in the model group,and the difference was statistically significant(P<0.05,P<0.01).Conclusion:Astragalus has multi-target,multi-component and multi-pathway action characteristics in the treatment of diabetic cardiomyopathy,which can exert anti-inflammatory and anti-oxidative stress effects by regulating protein expression of MAPK signaling pathway ERK1,p-p38.
文摘Objectives It is not fully clarified how diabetes mellitus induced cardiac dysfunction and myocardial ultrastructural changes in the early state.In the present study,we provided an integrated approach to investigate early changes in myocardial function of diabetic rabbits and assessed the structural alteration.Methods and Results Diabetes was induced by alloxan injection.After 30 days,echocardio- graphy and left ventricular cannulation were performed in dia- betic(D,n=8) and control rabbits(C,n= 10).After catheterization, animals were killed for histological studies.Hema-toxylin -eosin and Masson’s Trichrome staining of the heart were analyzed.The ultrastructure of left ventricle was also examined with electron microscopy.Echocardiography revealed that early diabetic cardiomyopathy had impaired LV diastolic function expressed by diminished E-waves,increased Awaves, E/A ratio reversion and increased E-wave deceleration time(EDT).Concurrently,LV end-diastolic pressure(LVEDP) and diastolic time constant(T) were increased,minimum dP/ dt(LV-dp/dt)was reduced,obtained through cardiac catheterization.There were no significant differences in LV ejection fraction(EF),LV peak systolic pressure(LVSP), or maximum dP/dt(LV + dp/dt).Qualitative light microscopy revealed no histologic changes in myocardium from diabetic rabbits.The most evident ultrastructural change was spotted myofibrillar damage,while interstitial fibrosis was slight.Conclusions These results suggest that early diabetic cardiomyopathy in animal model is characterized by left ventricular diastolic dysfunction,both impaired active relaxation and increased passive chamber stiffness.Whereas,left ventricular systolic function can remain normal.It might partly contribute to myofibrillar damage,but not myocardial fibrosis.
基金supported by the National Natural Science Foundation of China(Grant Nos.:21927808 and 81803483).
文摘Diabetic cardiomyopathy(DCM)is a metabolic disease and a leading cause of heart failure among people with diabetes.Mass spectrometry imaging(MSI)is a versatile technique capable of combining the molecular specificity of mass spectrometry(MS)with the spatial information of imaging.In this study,we used MSI to visualize metabolites in the rat heart with high spatial resolution and sensitivity.We optimized the air flow-assisted desorption electrospray ionization(AFADESI)-MSI platform to detect a wide range of metabolites,and then used matrix-assisted laser desorption ionization(MALDI)-MSI for increasing metabolic coverage and improving localization resolution.AFADESI-MSI detected 214 and 149 metabolites in positive and negative analyses of rat heart sections,respectively,while MALDI-MSI detected 61 metabolites in negative analysis.Our study revealed the heterogenous metabolic profile of the heart in a DCM model,with over 105 region-specific changes in the levels of a wide range of metabolite classes,including carbohydrates,amino acids,nucleotides,and their derivatives,fatty acids,glycerol phospholipids,carnitines,and metal ions.The repeated oral administration of ferulic acid during 20 weeks significantly improved most of the metabolic disorders in the DCM model.Our findings provide novel insights into the molecular mechanisms underlying DCM and the potential of ferulic acid as a therapeutic agent for treating this condition.
基金Supported by National Natural Science Foundation of China,No.82000276the Science and Technology Project of Jiangxi Provincial Health Commission,No.202310005.
文摘BACKGROUND Diabetic cardiomyopathy(DCM),which is a complication of diabetes,poses a great threat to public health.Recent studies have confirmed the role of NLRP3(NOD-like receptor protein 3)activation in DCM development through the inflammatory response.Teneligliptin is an oral hypoglycemic dipeptidyl peptidase-IV inhibitor used to treat diabetes.Teneligliptin has recently been reported to have anti-inflammatory and protective effects on myocardial cells.AIM To examine the therapeutic effects of teneligliptin on DCM in diabetic mice.METHODS Streptozotocin was administered to induce diabetes in mice,followed by treatment with 30 mg/kg teneligliptin.RESULTS Marked increases in cardiomyocyte area and cardiac hypertrophy indicator heart weight/tibia length reductions in fractional shortening,ejection fraction,and heart rate;increases in creatine kinase-MB(CK-MB),aspartate transaminase(AST),and lactate dehydrogenase(LDH)levels;and upregulated NADPH oxidase 4 were observed in diabetic mice,all of which were significantly reversed by teneligliptin.Moreover,NLRP3 inflammasome activation and increased release of interleukin-1βin diabetic mice were inhibited by teneligliptin.Primary mouse cardiomyocytes were treated with high glucose(30 mmol/L)with or without teneligliptin(2.5 or 5μM)for 24 h.NLRP3 inflammasome activation.Increases in CKMB,AST,and LDH levels in glucose-stimulated cardiomyocytes were markedly inhibited by teneligliptin,and AMP(p-adenosine 5‘-monophosphate)-p-AMPK(activated protein kinase)levels were increased.Furthermore,the beneficial effects of teneligliptin on hyperglycaemia-induced cardiomyocytes were abolished by the AMPK signaling inhibitor compound C.CONCLUSION Overall,teneligliptin mitigated DCM by mitigating activation of the NLRP3 inflammasome.
基金supported by grants from the National Natural Science Foundation of China(No.81874434 and No.81804053)Yangtze River Delta Traditional Chinese Medicine Endocrinology and Metabolic Disease Specialist Alliance(No.ZY2021-2023-0302).
文摘Objective Diabetic cardiomyopathy(DCM)represents a substantial risk factor for heart failure and increased mortality in individuals afflicted with diabetes mellitus(DM).DCM typically manifests as myocardial fibrosis,myocardial hypertrophy,and impaired left ventricular diastolic function.While the clinical utility of the Jianpi Qinghua(JPQH)formula has been established in treating diabetes and insulin resistance,its potential efficacy in alleviating diabetic cardiomyopathy remains uncertain.This study aims to investigate the impact and underlying molecular mechanisms of the JPQH formula(JPQHF)in ameliorating myocardial injury in nonobese diabetic rats,specifically focusing on apoptosis and inflammation.Methods Wistar rats were assigned as the normal control group(CON),while Goto-Kakizaki(GK)rats were randomly divided into three groups:DM,DM treated with the JPQHF,and DM treated with metformin(MET).Following a 4-week treatment regimen,various biochemical markers related to glucose metabolism,cardiac function,cardiac morphology,and myocardial ultrastructure in GK rats were assessed.RNA sequencing was utilized to analyze differential gene expression and identify potential therapeutic targets.In vitro experiments involved high glucose to induce apoptosis and inflammation in H9c2 cells.Cell viability was evaluated using CCK-8 assay,apoptosis was monitored via flow cytometry,and the production of inflammatory cytokines was measured using quantitative real-time PCR(qPCR)and ELISA.Protein expression levels were determined by Western blotting analysis.The investigation also incorporated the use of MAPK inhibitors to further elucidate the mechanism at both the transcriptional and protein levels.Results The JPQHF group exhibited significant reductions in interventricular septal thickness at end-systole(IVSs)and left ventricular internal diameter at end-systole and end-diastole(LVIDs and LVIDd).JPQHF effectively suppressed high glucose-induced activation of IL-1βand caspase 3 in cardiomyocytes.Furthermore,JPQHF downregulated the expression of myocardial JunB/c-Fos,which was upregulated in both diabetic rats and high glucose-treated H9c2 cells.Conclusion The JPQH formula holds promise in mitigating diabetic myocardial apoptosis and inflammation in cardiomyocytes by inhibiting JunB/c-Fos expression through suppressing the MAPK(p38 and ERK1/2)pathway.
基金Natural Science Foundation of Hebei Province:the Central Regulatory Mechanism of Tanshinone IIA on AngiotensinⅡInduced Sympathetic Excitation in Intermittent Hypoxia(No.H2019423136)Fundamental Research Funds for the Provisional Universities of Hebei University of Chinese Medicine:a Study on the Protective Mechanism of Hydrogen on Chronic Intermittent Hypoxiainduced Microglia Inflammatory Response(No.YTZ2019001)+1 种基金a Study on the Molecular Mechanism of Improving Effect Danggui Buxue Decoction on Vascular Endothelial Cell Senescence in Chronic Intermittent Hypoxia through Nrf2/HO-1 Signaling Pathway(No.YXTD2021005)Graduate Innovation Fund of Hebei University of Chinese Medicine:the Effect of Jinlida Granules on the Myocardial Improvement of Chronic Intermittent Hypoxia Aggravated Diabetic Cardiomyopathy in db/db Mice(No.XCXZZBS2022013)。
文摘OBJECTIVE:To examine the protective effect of ginsenoside Rb1(Rb1),the main component of Renshen(Radix Ginseng),on cardiomyopathy in db/db mice exposed to chronic intermittent hypoxia(CIH)and explore the potential underlying mechanism of Rb1 in treating diabetic cardiomyopathy(DCM).METHODS:The db/db mice were randomly separated into five groups:normal control group,model group,Rb120 mg/kg group,Rb140 mg/kg group,and glucagon-like peptide-1(GLP-1)group.Mice were exposed to aircondition or CIH for 8 weeks,and Rb1 and GLP-1 were administrated before CIH exposure every day.Oral glucose tolerance test(OGTT),intraperitoneal insulin tolerance test(IPITT),total cholesterol(TC),triglyceride(TG),and high-density lipoprotein cholesterol(HDL-C)were detected to evaluate glycolipid metabolism.The level of insulin was detected by a mouse enzyme-linked immunosorbent assay(ELISA).Cardiac function was detected by echocardiography,and myocardial pathology was observed by hematoxylin-eosin and Masson staining.The expression of collagenⅠand collagenⅢwas detected by immunohistochemistry.Adenosine monophosphate-activated protein kinase(AMPK)/Nrf2/heme oxygenase-1(HO-1)signaling pathway was detected by Western blot and immunofluorescence.RESULTS:Rb1 treatment could improve glucose tolerance and the level of cardiac function indexes,and inhibit the level of oxidative stress indexes and the expression of collagenⅠand collagenⅢ.Moreover,Rb1 treatment enhanced AMPK phosphorylation and increased Nrf2 and HO-1 expression.CONCLUSION:Rb1 treatment alleviated CIH-induced diabetic cardiomyopathy and glycolipid metabolism disorders in db/db mice by inhibiting oxidative stress and regulating the AMPK/Nrf2/HO-1 signaling pathway.
基金supported in part by American Diabetes Association(1-18-IBS-082 to LC,USA)the National Key R&D Program of China(2016YFC0900903 to YZ,China)。
文摘Herein,we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy(DCM)by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model.Advanced glycation end-products(AGEs),an important pathogenic factor of DCM,were found to induce ferroptosis in engineered cardiac tissues(ECTs),as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7 A11 levels.Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy.Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction.Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM.Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes.Nuclear factor erythroid 2-related factor 2(NRF2)activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7 A11 levels.The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase(AMPK)-dependent.These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM;sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation.This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.
基金supported by the National Natural Science Foundation of China(81730012,81872871,and 82070283)CAMS Innovation Fund for Medical Sciences(2020-I2M-5-003)。
文摘Diabetic cardiomyopathy(DCM)is a common complication in diabetic patients.The molecular mechanisms of DCM remain to be fully elucidated.The intronic long noncoding RNA of DACH1(lnc DACH1)has been demonstrated to be closely associated with heart failure and cardiac regeneration.In this study,we investigated the role of lnc DACH1 in DCM and the underlying molecular mechanisms.The expression of lnc DACH1 was increased in DCM hearts and in high glucose-treated cardiomyocytes.Knockout of lnc DACH1 reduced mitochondrial oxidative stress,cell apoptosis,cardiac fibrosis and hypertrophy,and improved cardiac function in DCM mice.Overexpression of lnc DACH1 exacerbated mitochondria-derived reactive oxygen species(ROS)level and apoptosis,decreased activity of manganese superoxide dismutase(Mn-SOD);while silencing of lnc DACH1 attenuated ROS production,mitochondrial dysfunction,cell apoptosis,and increased the activity of Mn-SOD in cardiomyocytes treated with high glucose.Lnc DACH1 directly bound to sirtuin3(SIRT3)and facilitated its degradation by ubiquitination,therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts.In addition,SIRT3 silencing abrogated the protective effects of lnc DACH1 deficiency in cardiomyocytes.In summary,lnc DACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated SIRT3 degradation in mouse hearts.Inhibition of lnc DACH1 represents a novel therapeutic strategy for the intervention of diabetic cardiomyopathy.
基金supported by grants from the National Natural Science Foundation of China(Nos.81822002,31771264,31800973)the Fundamental Research Funds for the Central Universities(No.2019kfyXMBZ035).
文摘Cardiovascular diseases account for approximately 80%of deaths among individuals with diabetes mellitus,with diabetic cardiomyopathy as the major diabetic cardiovascular complication.Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy,fibrosis,apoptosis,and other pathophysiological changes.Although glycemic control has long been at the center of diabetes therapy,multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes.This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level.This process is now referred to as hyperglycemic memory(HGM)phenomenon.We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.
基金Thanks to the Ministry of Science and Technology of China(Grant Nos.2018YFA0801100 and 2021YFF0702100 to H.-Y.W.and S.C.)the National Natural Science Foundation of China(Grant Nos.32025019 and 31970719 to S.C.,82000349 to C.Q.,32000800 to M.L.,82000736 to Q.C.,and 31971067 to H.-Y.W.)+1 种基金the Science and Technology Foundation of Jiangsu Province of China(Grant Nos.BK20200315(Basic Research Program)to C.Q.and BK20190305(Basic Research Program)to Q.C.)the Fundamental Research Funds for the Central Universities(Grant Nos.021414380524 to S.C.,021414380508 to C.Q.,and 021414380505 to Q.C.),for financial support.
文摘Diabetic cardiomyopathy(DCM)is currently a progressive and nonstoppable complication in type 2 diabetic patients.Metabolic insults and insulin resistance are involved in its pathogenesis;however,the underlying mechanisms are still not clearly understood.Here we show that calcium dysregulation can be both a cause and a consequence of cardiac insulin resistance that leads to DCM.A western diet induces the development of DCM through at least three phases in mice,among which an early phase depends on impaired Thr^(484)-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a(SERCA2a)elicited by insulin resistance.Mutation of SERCA2a-Thr^(484) to a nonphosphorylatable alanine delays calcium re-uptake into the sarcoplasmic reticulum in the cardiomyocytes and decreases cardiac function at the baseline.Importantly,this mutation blunts the early phase of DCM,but has no effect on disease progression in the following phases.Interestingly,impairment of sarcoplasmic reticulum calcium re-uptake caused by the SERCA2a-Thr^(484) mutation inhibited processing of insulin receptor precursor through FURIN convertase,resulting in cardiac insulin resistance.Collectively,these data reveal a bidirectional relationship between insulin resistance and impairment of calcium homeostasis,which may underlie the early pathogenesis of DCM.Our findings have therapeutic implications for early intervention of DCM.
基金supported by the Advanced Projects of Innovation Program for the Selected Returned Overseas Chinese Scholars,Anhui Province(2020LCX022).
文摘Myocardial fibrosis is an important manifestation of diabetic cardiomyopathy.This study investigated the potential mechanism of diabetic myocardial fibrosis.Male C57BL/6J and db/db mice aged 8 weeks were randomly divided into the diabetic(DB)and control groups.At 20 weeks,the mouse heart was harvested and subjected to hematoxylin-eosin staining(HE)and Masson staining to investigate the degree of fibrosis.The expressions of transforming growth factor-beta 1(TGF-β1),collagen-III,B-cell lymphoma-2(Bcl2),Bcl2-associated X protein(Bax),cleaved gasdermin D(GSDMD),cysteinyl aspartate specific proteinase-1(caspase-1),apoptosis-associated speck-like protein containing a CARD(ASC),and nucleotide-binding oligomerization domain(NOD)-like receptor 3(NLRP3)were measured by western blotting.Immunohistochemistry and TdT-mediated dUTP nick end labeling(TUNEL)staining were performed to analyze the development of apoptosis and pyroptosis.A significant increase in body weight and blood glucose in the DB group was observed.Myocardial pathological injury,fibrosis,apoptosis,and pyroptosis were more obvious and serious in the DB group.The expression of anti-apoptotic Bcl2 significantly decreased,while the expression levels of pro-apoptotic Bax,caspase-3,and pyroptosis-related proteins,such as cleaved GSDMD,and caspase-1 in the DB group were significantly increased.Pyroptosis and apoptosis were probably the main mechanisms that caused myocardial fibrosis in mice with diabetes.
