Objective:To explore the therapeutic efficacy of L-carvone from Mentha spicata L.leaf extracts against isoproterenol-induced cardiac hypertrophy in rats.Methods:Isoproterenol(5 mg/kg)was injected intraperitoneally int...Objective:To explore the therapeutic efficacy of L-carvone from Mentha spicata L.leaf extracts against isoproterenol-induced cardiac hypertrophy in rats.Methods:Isoproterenol(5 mg/kg)was injected intraperitoneally into rats for one month to induce cardiac hypertrophy.L-carvone(25 and 100 mg/kg)was administered orally to treat cardiac hypertrophy.The cardioprotective activity of L-carvone was evaluated by electrocardiogram,histopathological analysis as well as determination of biochemical parameters and enzymatic markers.Results:L-carvone from Mentha spicata L.at 25 and 100 mg/kg ameliorated isoproterenol-induced cardiac hypertrophy,as evidenced by reduced QRS interval on electrocardiogram,and decreased heart weight and heart index.In addition,both doses of L-carvone markedly lowered the levels of glucose,total protein,low-density lipoprotein cholesterol,aspartate transaminase,alanine transaminase,lactate dehydrogenase,creatine kinase MB,troponin-Ⅰ,N-terminal pro-B type natriuretic peptide and triglycerides while increasing high-density lipoprotein cholesterol and lipase level(P<0.05).Moreover,L-carvone alleviated contraction band necrosis,and reorganized the myofibrils with normal striations and myocytes as well as normal nuclei in cardiac histoarchitecture of rats with isoproterenol-induced cardiac hypertrophy.Conclusions:L-carvone from Mentha spicata L.leaf extract can restore abnormal cardiac function and may be further explored as a therapeutic agent against the deleterious effects of cardiac hypertrophy after further evaluation.展开更多
Objective:Cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading,but continuous cardiac hypertrophy can lead to cardiac remodeling and heart failure.Cardiac hypertrophy is mostly consider...Objective:Cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading,but continuous cardiac hypertrophy can lead to cardiac remodeling and heart failure.Cardiac hypertrophy is mostly considered reversible,and recent studies have indicated that decorin not only prevents cardiac fibrosis associated with hypertension,but also achieves therapeutic effects by blocking fibrosis-related signaling pathways.However,the mechanism of action of decorin remains unknown and unconfirmed.Methods:We determined the degree of myocardial hypertrophy by measuring the ratios of the heart weight/body weight and left ventricular weight/body weight,histological analysis and immunohistochemistry.Western blotting was performed to detect the expression levels of CaMKⅡ,p-CaMKⅡ and MEF-2 in the heart.Results:Our results confirmed that decorin can regulate the CaMKⅡ/MEF-2 signaling pathway,with inhibition thereof being similar to that of decorin in reducing cardiac hypertrophy.Conclusion:Taken together,the results of the present study showed that decorin induced cardiac hypertrophy by regulating the CaMKⅡ/MEF-2 signaling pathway in vivo,revealing a new therapeutic approach for the prevention of cardiac hypertrophy.展开更多
PRKAG2 cardiac syndrome(PS)is a rare inherited disease due to PRKAG2 gene mutation and characterized by Wolff-Parkinson-White syndrome(WPWs),conduction system lesions and myocardial hypertrophy.It can also lead to ser...PRKAG2 cardiac syndrome(PS)is a rare inherited disease due to PRKAG2 gene mutation and characterized by Wolff-Parkinson-White syndrome(WPWs),conduction system lesions and myocardial hypertrophy.It can also lead to serious consequences,such as sudden death.But the genetic and clinical heterogeneity makes the early diagnosis of PS difficult.Here we studied a family with familial hypertrophic cardiomyopathy and other diverse manifestations.Gene analysis identified a missense mutation(Arg302Gln)in the five affected subjects of the family.The electrocardiograph performance of the five was composed of sinus bradycardia(SB),WPWs,right bundle branch block(RBBB),atrioventricular block(AVB),left bundle branch block(LBBB),supraventricular tachycardia(SVT)and atrial premature beat(APB).Among them,the youngest one began to show paroxysmal palpitation at the age of nine and was confirmed to have WPWs at 17 years old;two members progressed over time to serious conduction damage,and the proband received a pacemaker at the age of 27 due to AVB.Besides,according to cardiac magnetic resonance and echocardiography,the youngest one showed symmetric hypertrophy;three older members showed asymmetric myocardial hypertrophy characterized with a diffuse pattern of middle-anterior-lateral-inferior wall hypertrophy and especially interventricular septal hypertrophy;all five affected patients showed atrial enlargement regardless of myocardial hypertrophy at an earlier stage.In conclusion,the conduction system disorder,familial atrial enlargement and symmetric cardiac hypertrophy may occur in the early stage of PRKAG2 R302Q mutation.展开更多
OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model ...OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.展开更多
Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta...Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta group (CAA), sham operation group (SH), and carvedilol intervention group (CAR+CAA, carvedilol 30mg·kg -1 ·day -1 orally) and carvedilol control group (CAR+SH). Hemodynamics, ventricular remodeling parameters, free fatty acid in blood serum and cardiac myocyte, RT PCR analysis of the expressions of Muscle Carnitine Palmitoyltransferase I (M CPT I) and Medium Chain Acyl CoA Dehydrogenase (MCAD) mRNA were measured in all rats at 16 week after operation. Results Left ventricular hypertrophy occurrd after operation 16 weeks in group of CAA, accompanying with plasma free fatty acids accumulation, and both the levels of M CPT I and MCADmRNA were decreased significantly ( P <0.05). Carvedilol can reduce the left ventricular hypertrophy induced by pressure overload. The gene expressions of rate limiting enzyme(M CPT I) and key enzyme of fatty acid (MCAD) were upregulated in the CAR+CAA group, comparing with CAA group ( P <0.05). There was no statistically significant difference between SH group and CAR + SH group. Pressure overload in CAA rats downregulates the gene expression of rate limiting enzyme and key enzyme of fatty acid oxidation. Conclusions The intervention with carvedilol may attenuates the reversion of the metabolic gene expression back towards fetal type through up regulating the expression of M CPT I and MCADmRNA. Thus, carvedilol may confer cardioprotective effects in heart failure partly by preserving of the normal metabolic gene regulation.展开更多
Objective:To investigate the effect of astragaloside IV on cardiac hypertrophy and its regulation on autophagy.Methods:Fifty male Sprague-Dawley rats were randomly divided into sham operation group and abdominal aorti...Objective:To investigate the effect of astragaloside IV on cardiac hypertrophy and its regulation on autophagy.Methods:Fifty male Sprague-Dawley rats were randomly divided into sham operation group and abdominal aortic coarctation group(AAC group).There were 10 rats in sham operation group and 40 rats in the AAC group.One week after the operation,there were 32 rats in AAC group,10 rats in sham group.AAC group was randomly divided into model group,low-dose astragaloside group,high-dose astragaloside group and rapamycin group,8 rats in each group.Rapamycin group was a positive autophagy contrast agent group.They were given the corresponding solvents once a day by gavage for six weeks.At the end of study,three rats were randomly selected from each group,left ventricular mass index(LVW/BW),cardiac mass index(HW/BW)and the content of hydroxyproline were measured.HE staining,masson staining and sirius red staining were used to observe the morphological changes of myocardium.The expression of LC3II,LC3I,Beclin1,AMPK and mTOR were detected by western blot.Results:Compared with the sham operation group,AAC group showed hypertrophy,LVW/BW,HW/BW,HYP and p-mTOR/mTOR were significantly increased(P<0.05),p-AMPK/AMPK,LC3II/LC3I,Beclin1 were significantly decreased(P<0.05).Compared with the model group,the low-dose astragaloside IV group showed the hypertrophy of cardiomyocytes was relatively light,LVW/BW and HW/BW were significantly decreased(P<0.05),there was no significant difference in HYP and p-mTOR/mTOR(P>0.05),LC3II/LC3I,Beclin1 and p-AMPK/AMPK were significantly increased(P<0.05).Compared with the model group,high-dose astragaloside IV group and rapamycin group showed reduced myocardial hypertrophy,LVW/BW,HW/BW,HYP and p-mTOR/mTOR were significantly decreased(P<0.05),LC3II/LC3I,Beclin1 and p-AMPK/AMPK were significantly increased(P<0.05).Compared with the low-dose astragaloside group,the high-dose astragaloside group showed reduced myocardial hypertrophy,there were significant differences in each index(P<0.05).Compared with rapamycin group,there was no obvious difference in morphology and structure of myocardial cells,LVW/BW,HYP and p-mTOR/mTOR were decreased(P<0.05),HW/BW and p-AMPK/AMPK had no significant difference(P>0.05),LC3II/LC3I and Beclin1 were increased in high-dose astragaloside group(P<0.05).Conclusion:As IV has protective effect on cardiac hypertrophy in a dose-dependent manner and its mechanism may be related to regulate autophagy.展开更多
MicroRNAs(miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression post-transcriptionally. Recent studies have demonstrated that miRNAs are involved in the pathogenesis of hypertrophy.We in...MicroRNAs(miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression post-transcriptionally. Recent studies have demonstrated that miRNAs are involved in the pathogenesis of hypertrophy.We investigated miR-16 expression and their potential roles in a rat model of hypertrophy induced by abdominal artery constriction (AAC).miR-16 expression was significantly decreased, and CCND1 and CCND2 protein were markedly increased without obvious change of its mRNA level after hypertrophy induction.CCND1 and CCND2 levels were increased without changing their transcript levels in neonatal rat ventricular cardiomyocytes(NRVC) induced by PE,and miR-16 was down-regulated in this process with significantly up-regulatedβ-MHC,ANF and MLC-2 expression.Conversely,introduction of functional miR-16,CCND1 siRNA or CCND2 siRNA into NRVCs could repress cardiomyocyte hypertrophy.These results implicate that miR-16 is involved in contributing to cardiac hypertrophy,one of the mechanisms may be resulted from post-transcriptional regulation of CCND1 and CCND2.展开更多
The gut microbiota is involved in host responses to high altitude.However,the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood.Here,we used a rat model of h...The gut microbiota is involved in host responses to high altitude.However,the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood.Here,we used a rat model of hypobaric hypoxia challenge to mimic plateau exposure and monitored the gut microbiome,short-chain fatty acids(SCFAs),and bile acids(BAs)over 28 d.We identified weight loss,polycythemia,and pathological cardiac hypertrophy in hypoxic rats,accompanied by a large compositional shift in the gut microbiota,which is mainly driven by the bacterial families of Prevotellaceae,Porphyromonadaceae,and Streptococcaceae.The aberrant gut microbiota was characterized by increased abundance of the Parabacteroides,Alistipes,and Lactococcus genera and a larger Bacteroides to Prevotella ratio.Trans-omics analyses showed that the gut microbiome was significantly correlated with the metabolic abnormalities of SCFAs and BAs in feces,suggesting an interaction network remodeling of the microbiome-metabolome after the hypobaric hypoxia challenge.Interestingly,the transplantation of fecal microbiota significantly increased the diversity of the gut microbiota,partially inhibited the increased abundance of the Bacteroides and Alistipes genera,restored the decrease of plasma propionate,and moderately ameliorated cardiac hypertrophy in hypoxic rats.Our results provide an insight into the longitudinal changes in intestinal microecology during the hypobaric hypoxia challenge.Abnormalities in the gut microbiota and microbial metabolites contribute to the development of high-altitude heart disease in rats.展开更多
Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes...Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34 c-5 p on cardiac hypertrophy and the mechanism involved. The expression of miR-34 c-5 p was proved to be elevated in heart tissues from isoprenaline(ISO)-infused mice. ISO also promoted miR-34 c-5 p level in primary cultures of neonatal rat cardiomyocytes(NRCMs). Transfection with miR-34 c-5 p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor(Anf) and β-myosin heavy chain(β-Mhc) in NRCMs. In contrast, treatment with miR-34 c-5 p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34 c-5 p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34 c-5 p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34 c-5 p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4 B(ATG4 B) was identified as a direct target of miR-34 c-5 p, and miR-34 c-5 p was certified to interact with 3’untranslated region of Atg4 b mRNA by dual-luciferase reporter assay. miR-34 c-5 p reduced the expression of ATG4 B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34 c-5 p abolished the detrimental effects of ISO by restoring ATG4 B and increasing autophagy. In conclusion, our findings illuminate that miR-34 c-5 p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4 B and autophagy. It suggests that regulation of miR-34 c-5 p may offer a new way for handling hypertrophy-related cardiac dysfunction.展开更多
MicroRNAs(miRNAs)are endogenous small non-coding RNA molecules that posttranscriptionally regulate gene expression.MiRNA expression and function in heart disease remain to be determined but modulation of miRNA express...MicroRNAs(miRNAs)are endogenous small non-coding RNA molecules that posttranscriptionally regulate gene expression.MiRNA expression and function in heart disease remain to be determined but modulation of miRNA expression in vivo has revealed that miRNAs play an important role in controlling heart function and structure.In fact,abnormal expression of miRNAs may initiate and contribute to the progress of heart disease.Here,we summarize the literature relating to the involvement of miRNAs in cardiac hypertrophy,myocardial fibrosis and heart failure.展开更多
Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure....Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase(PON) gene cluster(PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene(PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type(WT) control. The same protective tendency was also observed with an Apoe^(-/-)background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases(MMPs)/tissue inhibitors of MMPs(TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.展开更多
Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study i...Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study is to test whether 5-HT_(3) receptor antagonists protect against cardiac hypertrophy.Cardiac hypertrophy induced by TAC for 4 weeks in mice was significantly inhibited by administration of 5-HT_(3) receptor antagonists,ondansetron(2.5 mg/kg,ip.)or tropisetron(2.5 mg/kg,ip.).Histological analysis revealed that the increased cardiac fibrosis in hypertrophic heart was relieved by ondansetron or tropisetron treatment.Ondansetron or tropisetron reduced the elevated plasma level of noradrenalin in mice with cardiac hypertrophy.Ondansetron and tropisetron had no effect on cardiomyocte hypertrophy induced by phenylephrine treatment in vitro.Finally,we took tropisetron as the representative drug and examined the effects of tropisetron on the desensitization of cardiac b-adrenergic receptor in rat treated with abdominal aortic banding(AB).Results showed that tropisetron restored the desensitization of cardiac b-adrenergic receptor in AB-treated rats.In conclusion,5-HT_(3) receptor antagonists protected against cardiac hypertrophy and restored the desensitization of cardiac adrenergic responsiveness,the mechanism in which may be through reducing the sympathetic activity.展开更多
The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphor...The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases II(Pol II)and leading to transcription elongation.The present study identified a novel post-translational modification of BRD4:poly(ADPribosyl)ation(PARylation),that was mediated by poly(ADP-ribose)polymerase-1(PARP1)in cardiac hypertrophy.BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol(ISO),whereas overexpression of BRD4 promoted cardiac hypertrophy,confirming the critical role of BRD4 in pathological cardiac hypertrophy.PARP1 was activated in ISOinduced cardiac hypertrophy and facilitated the development of cardiac hypertrophy.BRD4 was involved in the prohypertrophic effect of PARP1,as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses,and that BRD4 overexpression suppressed the antihypertrophic effect of PARP1 inhibitors.Interactions of BRD4 and PARP1 were observed by coimmunoprecipitation and immunofluorescence.PARylation of BRD4 induced by PARP1 was investigated by PARylation assays.In response to hypertrophic stimuli like ISO,PARylation level of BRD4 was elevated,along with enhanced interactions between BRD4 and PARP1.By investigating the PARylation of truncation mutants of BRD4,the C-terminal domain(CTD)was identified as the PARylation modification sites of BRD4.PARylation of BRD4 facilitated its binding to the transcription start sites(TSS)of hypertrophic genes,resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes.The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.展开更多
Background Cardiac hypertrophy(CH)is a pathological state of heart which could lead to arrhythmias,cardiac failure,and sudden cardiac death.Pathology of cardiac hypertrophy has been acknowledged widely,but the detaile...Background Cardiac hypertrophy(CH)is a pathological state of heart which could lead to arrhythmias,cardiac failure,and sudden cardiac death.Pathology of cardiac hypertrophy has been acknowledged widely,but the detailed molecular mechanism has not been explored thoroughly.Our study was designed to identify differentially expressed genes(DEGs),and to explore the molecular mechanism and core genes that may be involved in the progression of cardiac hypertrophy.Methods Microarray data of cardiac hypertrophy(GSE76)was downloaded from the Gene Expression Omnibus(GEO)database.The DEGs were identified by R.Then Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis and protein-protein interaction(PPI)network analyses were performed by DAVID,STRING and Cytoscape.Results 1014 DEGs in GSE76 were identified,970 were downregulated genes and 44 were upregulated genes in cardiac hypertrophic tissues.The biological process(BP)analysis revealed that DEGs mainly included genes for inflammatory response,cell adhesion,and cell proliferation.The core genes were associated with cardiac remodeling and fibrosis,cell growth,inflammatory reaction,and cell adhesion.Conclusions This study indicated the potential significance of immune injury and cardiac fibrosis in the progression of cardiac hypertrophy.Meanwhile,the core genes may provide molecular targets for the disease diagnosis or drug treatment of cardiac hypertrophy in the future.展开更多
Background:Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart.Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocy...Background:Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart.Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes.However,it remains unclear whether and how lymphangiogenesis contributes to exercise-induced physiological cardiac growth.We aimed to investigate the role and mechanism of lymphangiogenesis in exercise-induced physiological cardiac growth.Methods:Adult C57 BL6/J mice were subjected to 3 weeks of swimming exercise to induce physiological cardiac growth.Oral treatment with vascular endothelial growth factor receptor 3(VEGFR3) inhibitor SAR1 3 1 675 was used to investigate whether cardiac lymphangiogenesis was required for exercise-induced physiological cardiac growth by VEGFR3 activation.Furthermore,human dermal lymphatic endothelial cell(LEC)-conditioned medium was collected to culture isolated neonatal rat cardiomyocytes to determine whether and how LECs could influence cardiomyocyte proliferation and hypertrophy.Results:Swimming exercise induced physiological cardiac growth accompanied by a remarkable increase of cardiac lymphangiogenesis as evidenced by increased density of lymphatic vessel endothelial hyaluronic acid receptor 1-positive lymphatic vessels in the heart and upregulated LYVE-1 and Podoplanin expressions levels.VEGFR3 was upregulated in the exercised heart,while VEGFR3 inhibitor SAR131675 attenuated exercise-induced physiological cardiac growth as evidenced by blunted myocardial hypertrophy and reduced proliferation marker Ki67 in cardiomyocytes,which was correlated with reduced lymphatic vessel density and downregulated LYVE-1 and Podoplanin in the heart upon exercise.Furthermore,LEC-conditioned medium promoted both hypertrophy and proliferation of cardiomyocytes and contained higher levels of insulinlike growth factor-1 and the extracellular protein Reelin,while LEC-conditioned medium from LECs treated with SAR131675 blocked these effects.Functional rescue assays further demonstrated that protein kinase B(AKT) activation,as well as reduced CCAAT enhancer-binding protein beta(C/EBPβ) and increased CBP/p300-interacting transactivators with E(glutamic acid)/D(aspartic acid)-rich-carboxylterminal domain 4(CITED4),contributed to the promotive effect of LEC-conditioned medium on cardiomyocyte hypertrophy and proliferation.Conclusion:Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation,and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis.These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth.展开更多
Free fatty acids(FFAs)play important roles in cardiovascular disease.Studies have shown that it is an important way for FAs to exert biological effects through their own receptors besides directly participating bioche...Free fatty acids(FFAs)play important roles in cardiovascular disease.Studies have shown that it is an important way for FAs to exert biological effects through their own receptors besides directly participating biochemical reaction in body.Free fatty acid receptor 2(FFA2)can be activated by short-chain FAs and is involved in inflammatory reactions and lipid accumulation.Since the known pathological changes caused by FFA2 are also implicated in cardiac hypertrophy,we hypothesized that FFA2 might be pathogenic in cardiac hypertrophy.This paper showed that FFA2 expression significantly increased in cardiac hypertrophy in vivo and in vitro.FFA2 agonist 4-CMTB or TUG-1375 promoted the expression of the hypertrophy markers ANF and BNP and increased cell surface area in vitro,which was further strengthened by FFA2 overexpression,suggesting that FFA2 might contribute to cardiomyocyte hypertrophy.Furthermore,4-CMTB treatment or FFA2 overexpression combined with 4-CMTB treatment elevated the phosphorylation and transcriptional activity of GATA4 and STAT3,which were inhibited by an ERK1/2 inhibitor,and GATA4 and STAT3 knockdown inhibited the elevation of hypertrophy biomarkers in cardiomyocytes treated with 4-CMTB.Taken together,these data indicate that FFA2 can enhance cardiomyocyte hypertrophy by activating STAT3 and GATA4 via ERK1/2,providing a potential new target for therapy.展开更多
Background:Visceral adipose tissue-derived serine protease inhibitor(vaspin),a secretory adipokine,protects against insulin resistance.Recent studies have demonstrated that serum vaspin levels are decreased in patient...Background:Visceral adipose tissue-derived serine protease inhibitor(vaspin),a secretory adipokine,protects against insulin resistance.Recent studies have demonstrated that serum vaspin levels are decreased in patients with coronary artery disease and that vaspin protects against myocardial ischemia-reperfusion injury and atherosclerosis.However,it remains unclear whether vaspin exerts specific effects on pathological cardiac hypertrophy.Methods:An in vivo study was conducted using a cardiac hypertrophy model established by subcutaneous injection of isoproterenol(ISO)in C57BL/6 and vaspin-ko mice.Rapamycin was administered intraperitoneally to mice,for further study.H9c2 cells and neonatal rat ventricular myocytes(NRVMs)were treated with ISO to induce hypertrophy.Human vaspin fusion protein,the proteasome inhibitor MG132,and chloroquine diphosphate were used for further mechanistic studies.Results:Here,we provide the first evidence that vaspin knockdown results in markedly exaggerated cardiac hypertrophy,fibrosis,and cardiomyocyte senescence in mice treated with ISO.Conversely,the administration of exogenous recombinant human vaspin protected NRVMs in vitro against ISO-induced hypertrophy and senescence.Furthermore,vaspin significantly potentiated the ISO-induced decrease in autophagy.Both rapamycin and chloroquine diphosphate regulated autophagy in vivo and in vitro,respectively,and participated in vaspin-mediated cardioprotection.Moreover,the PI3K-AKT-mTOR pathway plays a critical role in vaspin-mediated autophagy in cardiac tissues and NRVMs.Our data showed that vaspin downregulated the p85 and p110 subunits of PI3K by linking p85 and p110 to NEDD4L-mediated ubiquitination degradation.Conclusion:Our results show,for the first time,that vaspin functions as a critical regulator that alleviates pathological cardiac hypertrophy by regulating autophagy-dependent myocardial senescence,providing potential preventive and therapeutic targets for pathological cardiac hypertrophy.展开更多
Objective:To investigate the effects of cagliazin,a sodium-glucose cotransporter 2 inhibitor(SGLT-2I),on ventricular remodeling in spontaneously hypertensive rats(SHR)through renin angiotensin system(RAS)and transform...Objective:To investigate the effects of cagliazin,a sodium-glucose cotransporter 2 inhibitor(SGLT-2I),on ventricular remodeling in spontaneously hypertensive rats(SHR)through renin angiotensin system(RAS)and transforming growth factor-β1(TGF-β1).Methods:The experiment was divided into 4 groups:normal blood pressure control group,SHR group,cagliet net low-dose group(30mg/kg),cagliet net high-dose group(60mg/kg),once a day for 8 weeks.Normal blood pressure rats(WKY)were used as the control group to measure blood pressure with tail sleeve sphygmomanometer(BP)and blood glucose level was measured with glucose meter Cardiac function was evaluated by echocardiography,cell area of left ventricle was evaluated by histomorphology,real-time quantitative polymerase chain reaction and protein imprinting hybridization were used to detect TGF-β1 Smad4 renin from type I collagen(Col1a)type III collagen(Col3a)matrix metalloproteinase 2(MMP-2)Expression results of angiotensin II1 type receptor 1(AGTR1)and Angiotensin II2 type receptor 2(AGTR2).Results:After 8 weeks of administration,the cardiac weight/body weight ratio(HW/BW)of left ventricular weight/heart weight ratio(LVW/HW)of kaglinet low-dose group and high-dose group was statistically significant compared with that of spontaneous hypertensive rats(P<);Compared with SHRs,the expression of Col1a,Col3a,MMP2,TGF-β1,Smad4,Renin AGTR1 was significantly down-regulated and the expression of AGTR2 was up-regulated in cagliet net low-dose and high-dose groups Conclusions:Cagliazin can improve hypertension-induced cardiac remodeling by regulating RAS and TGF-β1/Smad signaling pathways.Conclusion:From the results,canaglifozin was found to ameliorate pressure overload-induced cardiac remodeling by regulating the RAS and TGF-β1/Smad signaling pathway.展开更多
Cardiovascular diseases are the leading cause of death worldwide. Cardiomyocytes are capable of coordinatedcontractions, which are mainly responsible for pumping blood. When cardiac stress occurs, cardiomyocytesunderg...Cardiovascular diseases are the leading cause of death worldwide. Cardiomyocytes are capable of coordinatedcontractions, which are mainly responsible for pumping blood. When cardiac stress occurs, cardiomyocytesundergo transition from physiological homeostasis to hypertrophic growth, proliferation, or apoptosis. During theseprocesses, many cellular factors and signaling pathways participate. PTEN is a ubiquitous dual-specificityphosphatase and functions by dephosphorylating target proteins or lipids, such as PIP3, a second messenger in thePI3K/AKT signaling pathway. Downregulation of PTEN expression or inhibiting its biologic activity improves heartfunction, promotes cardiomyocytes proliferation, reduces cardiac fibrosis as well as dilation, and inhibits apoptosisfollowing ischemic stress such as myocardial infarction. Inactivation of PTEN exhibits a potentially beneficialtherapeutic effects against cardiac diseases. In this review, we summarize various strategies for PTEN inactivationand highlight the roles of PTEN-less in regulating cardiomyocytes during cardiac development and stress responses.展开更多
Background Myocardial hypertrophy is an adaptive and compensatory response to pathological changes caused by circulatory overload and various factors.Myocardial hypertrophy have been a hot research topic in the field ...Background Myocardial hypertrophy is an adaptive and compensatory response to pathological changes caused by circulatory overload and various factors.Myocardial hypertrophy have been a hot research topic in the field of cardiovascular medicine.The research mainly involves the mechanism of myocardial hypertrophy and the development of effective drugs to prevent or slow down myocardial hypertrophy and myocardial remodeling.A large number of studies have shown that many Chinese medicine monomers may play a role in preventing the occurrence of myocardial hypertrophy.In order to understand the perspectives and development of traditional Chinese medicine monomers in the treatment of myocardial hypertrophy,this article reviewed the mechanism of various traditional Chinese medicine monomers in the treatment of myocardial hypertrophy.[S Chin J Cardiol 2021;22(1):65-68]展开更多
文摘Objective:To explore the therapeutic efficacy of L-carvone from Mentha spicata L.leaf extracts against isoproterenol-induced cardiac hypertrophy in rats.Methods:Isoproterenol(5 mg/kg)was injected intraperitoneally into rats for one month to induce cardiac hypertrophy.L-carvone(25 and 100 mg/kg)was administered orally to treat cardiac hypertrophy.The cardioprotective activity of L-carvone was evaluated by electrocardiogram,histopathological analysis as well as determination of biochemical parameters and enzymatic markers.Results:L-carvone from Mentha spicata L.at 25 and 100 mg/kg ameliorated isoproterenol-induced cardiac hypertrophy,as evidenced by reduced QRS interval on electrocardiogram,and decreased heart weight and heart index.In addition,both doses of L-carvone markedly lowered the levels of glucose,total protein,low-density lipoprotein cholesterol,aspartate transaminase,alanine transaminase,lactate dehydrogenase,creatine kinase MB,troponin-Ⅰ,N-terminal pro-B type natriuretic peptide and triglycerides while increasing high-density lipoprotein cholesterol and lipase level(P<0.05).Moreover,L-carvone alleviated contraction band necrosis,and reorganized the myofibrils with normal striations and myocytes as well as normal nuclei in cardiac histoarchitecture of rats with isoproterenol-induced cardiac hypertrophy.Conclusions:L-carvone from Mentha spicata L.leaf extract can restore abnormal cardiac function and may be further explored as a therapeutic agent against the deleterious effects of cardiac hypertrophy after further evaluation.
文摘Objective:Cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading,but continuous cardiac hypertrophy can lead to cardiac remodeling and heart failure.Cardiac hypertrophy is mostly considered reversible,and recent studies have indicated that decorin not only prevents cardiac fibrosis associated with hypertension,but also achieves therapeutic effects by blocking fibrosis-related signaling pathways.However,the mechanism of action of decorin remains unknown and unconfirmed.Methods:We determined the degree of myocardial hypertrophy by measuring the ratios of the heart weight/body weight and left ventricular weight/body weight,histological analysis and immunohistochemistry.Western blotting was performed to detect the expression levels of CaMKⅡ,p-CaMKⅡ and MEF-2 in the heart.Results:Our results confirmed that decorin can regulate the CaMKⅡ/MEF-2 signaling pathway,with inhibition thereof being similar to that of decorin in reducing cardiac hypertrophy.Conclusion:Taken together,the results of the present study showed that decorin induced cardiac hypertrophy by regulating the CaMKⅡ/MEF-2 signaling pathway in vivo,revealing a new therapeutic approach for the prevention of cardiac hypertrophy.
文摘PRKAG2 cardiac syndrome(PS)is a rare inherited disease due to PRKAG2 gene mutation and characterized by Wolff-Parkinson-White syndrome(WPWs),conduction system lesions and myocardial hypertrophy.It can also lead to serious consequences,such as sudden death.But the genetic and clinical heterogeneity makes the early diagnosis of PS difficult.Here we studied a family with familial hypertrophic cardiomyopathy and other diverse manifestations.Gene analysis identified a missense mutation(Arg302Gln)in the five affected subjects of the family.The electrocardiograph performance of the five was composed of sinus bradycardia(SB),WPWs,right bundle branch block(RBBB),atrioventricular block(AVB),left bundle branch block(LBBB),supraventricular tachycardia(SVT)and atrial premature beat(APB).Among them,the youngest one began to show paroxysmal palpitation at the age of nine and was confirmed to have WPWs at 17 years old;two members progressed over time to serious conduction damage,and the proband received a pacemaker at the age of 27 due to AVB.Besides,according to cardiac magnetic resonance and echocardiography,the youngest one showed symmetric hypertrophy;three older members showed asymmetric myocardial hypertrophy characterized with a diffuse pattern of middle-anterior-lateral-inferior wall hypertrophy and especially interventricular septal hypertrophy;all five affected patients showed atrial enlargement regardless of myocardial hypertrophy at an earlier stage.In conclusion,the conduction system disorder,familial atrial enlargement and symmetric cardiac hypertrophy may occur in the early stage of PRKAG2 R302Q mutation.
基金National Natural Science Foundation of China(81860732)Scientific and Technological Projects for Social Development in Guizhou Province of China([2011]3036)the State Key Laboratory of Cardiovascular Disease(2017kf-03)
文摘OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.
文摘Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta group (CAA), sham operation group (SH), and carvedilol intervention group (CAR+CAA, carvedilol 30mg·kg -1 ·day -1 orally) and carvedilol control group (CAR+SH). Hemodynamics, ventricular remodeling parameters, free fatty acid in blood serum and cardiac myocyte, RT PCR analysis of the expressions of Muscle Carnitine Palmitoyltransferase I (M CPT I) and Medium Chain Acyl CoA Dehydrogenase (MCAD) mRNA were measured in all rats at 16 week after operation. Results Left ventricular hypertrophy occurrd after operation 16 weeks in group of CAA, accompanying with plasma free fatty acids accumulation, and both the levels of M CPT I and MCADmRNA were decreased significantly ( P <0.05). Carvedilol can reduce the left ventricular hypertrophy induced by pressure overload. The gene expressions of rate limiting enzyme(M CPT I) and key enzyme of fatty acid (MCAD) were upregulated in the CAR+CAA group, comparing with CAA group ( P <0.05). There was no statistically significant difference between SH group and CAR + SH group. Pressure overload in CAA rats downregulates the gene expression of rate limiting enzyme and key enzyme of fatty acid oxidation. Conclusions The intervention with carvedilol may attenuates the reversion of the metabolic gene expression back towards fetal type through up regulating the expression of M CPT I and MCADmRNA. Thus, carvedilol may confer cardioprotective effects in heart failure partly by preserving of the normal metabolic gene regulation.
基金Scientific Research Project of Sichuan Education Department(No.14ZA0137)。
文摘Objective:To investigate the effect of astragaloside IV on cardiac hypertrophy and its regulation on autophagy.Methods:Fifty male Sprague-Dawley rats were randomly divided into sham operation group and abdominal aortic coarctation group(AAC group).There were 10 rats in sham operation group and 40 rats in the AAC group.One week after the operation,there were 32 rats in AAC group,10 rats in sham group.AAC group was randomly divided into model group,low-dose astragaloside group,high-dose astragaloside group and rapamycin group,8 rats in each group.Rapamycin group was a positive autophagy contrast agent group.They were given the corresponding solvents once a day by gavage for six weeks.At the end of study,three rats were randomly selected from each group,left ventricular mass index(LVW/BW),cardiac mass index(HW/BW)and the content of hydroxyproline were measured.HE staining,masson staining and sirius red staining were used to observe the morphological changes of myocardium.The expression of LC3II,LC3I,Beclin1,AMPK and mTOR were detected by western blot.Results:Compared with the sham operation group,AAC group showed hypertrophy,LVW/BW,HW/BW,HYP and p-mTOR/mTOR were significantly increased(P<0.05),p-AMPK/AMPK,LC3II/LC3I,Beclin1 were significantly decreased(P<0.05).Compared with the model group,the low-dose astragaloside IV group showed the hypertrophy of cardiomyocytes was relatively light,LVW/BW and HW/BW were significantly decreased(P<0.05),there was no significant difference in HYP and p-mTOR/mTOR(P>0.05),LC3II/LC3I,Beclin1 and p-AMPK/AMPK were significantly increased(P<0.05).Compared with the model group,high-dose astragaloside IV group and rapamycin group showed reduced myocardial hypertrophy,LVW/BW,HW/BW,HYP and p-mTOR/mTOR were significantly decreased(P<0.05),LC3II/LC3I,Beclin1 and p-AMPK/AMPK were significantly increased(P<0.05).Compared with the low-dose astragaloside group,the high-dose astragaloside group showed reduced myocardial hypertrophy,there were significant differences in each index(P<0.05).Compared with rapamycin group,there was no obvious difference in morphology and structure of myocardial cells,LVW/BW,HYP and p-mTOR/mTOR were decreased(P<0.05),HW/BW and p-AMPK/AMPK had no significant difference(P>0.05),LC3II/LC3I and Beclin1 were increased in high-dose astragaloside group(P<0.05).Conclusion:As IV has protective effect on cardiac hypertrophy in a dose-dependent manner and its mechanism may be related to regulate autophagy.
文摘MicroRNAs(miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression post-transcriptionally. Recent studies have demonstrated that miRNAs are involved in the pathogenesis of hypertrophy.We investigated miR-16 expression and their potential roles in a rat model of hypertrophy induced by abdominal artery constriction (AAC).miR-16 expression was significantly decreased, and CCND1 and CCND2 protein were markedly increased without obvious change of its mRNA level after hypertrophy induction.CCND1 and CCND2 levels were increased without changing their transcript levels in neonatal rat ventricular cardiomyocytes(NRVC) induced by PE,and miR-16 was down-regulated in this process with significantly up-regulatedβ-MHC,ANF and MLC-2 expression.Conversely,introduction of functional miR-16,CCND1 siRNA or CCND2 siRNA into NRVCs could repress cardiomyocyte hypertrophy.These results implicate that miR-16 is involved in contributing to cardiac hypertrophy,one of the mechanisms may be resulted from post-transcriptional regulation of CCND1 and CCND2.
基金supported by the National Natural Science Foundation of China(81790632,31970863,and 31970088)the National Key Technology Research and Development Program of the Ministry of Science and Technology of China(2020YFA0509600)。
文摘The gut microbiota is involved in host responses to high altitude.However,the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood.Here,we used a rat model of hypobaric hypoxia challenge to mimic plateau exposure and monitored the gut microbiome,short-chain fatty acids(SCFAs),and bile acids(BAs)over 28 d.We identified weight loss,polycythemia,and pathological cardiac hypertrophy in hypoxic rats,accompanied by a large compositional shift in the gut microbiota,which is mainly driven by the bacterial families of Prevotellaceae,Porphyromonadaceae,and Streptococcaceae.The aberrant gut microbiota was characterized by increased abundance of the Parabacteroides,Alistipes,and Lactococcus genera and a larger Bacteroides to Prevotella ratio.Trans-omics analyses showed that the gut microbiome was significantly correlated with the metabolic abnormalities of SCFAs and BAs in feces,suggesting an interaction network remodeling of the microbiome-metabolome after the hypobaric hypoxia challenge.Interestingly,the transplantation of fecal microbiota significantly increased the diversity of the gut microbiota,partially inhibited the increased abundance of the Bacteroides and Alistipes genera,restored the decrease of plasma propionate,and moderately ameliorated cardiac hypertrophy in hypoxic rats.Our results provide an insight into the longitudinal changes in intestinal microecology during the hypobaric hypoxia challenge.Abnormalities in the gut microbiota and microbial metabolites contribute to the development of high-altitude heart disease in rats.
基金supported by grants from the National Natural Science Foundation of China (81872860,81673433,and82070268)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093,China)+4 种基金National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104,China)National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province,2017B090903004,China)Special Program for Applied Science and Technology of Guangdong Province (2015B020232009,China)Guangdong Basic and Applied Basic Research Foundation(2020A1515011512,China)Young Teacher Training Program of Sun Yat-sen University (18ykpy26,China)。
文摘Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34 c-5 p on cardiac hypertrophy and the mechanism involved. The expression of miR-34 c-5 p was proved to be elevated in heart tissues from isoprenaline(ISO)-infused mice. ISO also promoted miR-34 c-5 p level in primary cultures of neonatal rat cardiomyocytes(NRCMs). Transfection with miR-34 c-5 p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor(Anf) and β-myosin heavy chain(β-Mhc) in NRCMs. In contrast, treatment with miR-34 c-5 p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34 c-5 p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34 c-5 p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34 c-5 p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4 B(ATG4 B) was identified as a direct target of miR-34 c-5 p, and miR-34 c-5 p was certified to interact with 3’untranslated region of Atg4 b mRNA by dual-luciferase reporter assay. miR-34 c-5 p reduced the expression of ATG4 B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34 c-5 p abolished the detrimental effects of ISO by restoring ATG4 B and increasing autophagy. In conclusion, our findings illuminate that miR-34 c-5 p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4 B and autophagy. It suggests that regulation of miR-34 c-5 p may offer a new way for handling hypertrophy-related cardiac dysfunction.
基金supported by the China Postdoctoral Special Science Foundation,the Foundation for the Author of a National Excellent Doctoral Dissertation of P.R.China(2007B72)the National Basic Research Program of China(2007CB512006)。
文摘MicroRNAs(miRNAs)are endogenous small non-coding RNA molecules that posttranscriptionally regulate gene expression.MiRNA expression and function in heart disease remain to be determined but modulation of miRNA expression in vivo has revealed that miRNAs play an important role in controlling heart function and structure.In fact,abnormal expression of miRNAs may initiate and contribute to the progress of heart disease.Here,we summarize the literature relating to the involvement of miRNAs in cardiac hypertrophy,myocardial fibrosis and heart failure.
基金supported by the National Natural Science Foundation of China(81422002,91339201,31271227,31571193)the National Science and Technology Support Project(2013YQ0309230502,2014BAI02B01)the Beijing Nova Program(XX2013064)
文摘Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase(PON) gene cluster(PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene(PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type(WT) control. The same protective tendency was also observed with an Apoe^(-/-)background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases(MMPs)/tissue inhibitors of MMPs(TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.
基金This work was supported by National Natural Science Foundation of China(30873064)Foundation of Key Laboratory of Bio-pharmaceutical-engineering(Harbin Medical University),Ministry of Education(2010-07).
文摘Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study is to test whether 5-HT_(3) receptor antagonists protect against cardiac hypertrophy.Cardiac hypertrophy induced by TAC for 4 weeks in mice was significantly inhibited by administration of 5-HT_(3) receptor antagonists,ondansetron(2.5 mg/kg,ip.)or tropisetron(2.5 mg/kg,ip.).Histological analysis revealed that the increased cardiac fibrosis in hypertrophic heart was relieved by ondansetron or tropisetron treatment.Ondansetron or tropisetron reduced the elevated plasma level of noradrenalin in mice with cardiac hypertrophy.Ondansetron and tropisetron had no effect on cardiomyocte hypertrophy induced by phenylephrine treatment in vitro.Finally,we took tropisetron as the representative drug and examined the effects of tropisetron on the desensitization of cardiac b-adrenergic receptor in rat treated with abdominal aortic banding(AB).Results showed that tropisetron restored the desensitization of cardiac b-adrenergic receptor in AB-treated rats.In conclusion,5-HT_(3) receptor antagonists protected against cardiac hypertrophy and restored the desensitization of cardiac adrenergic responsiveness,the mechanism in which may be through reducing the sympathetic activity.
基金supported by grants from the National Natural Science Foundation of China(81872860,81673433,and 81973318)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)+6 种基金National Major Special Projects for the Creation and Manufacture of New Drugs(2019ZX09301104,China)Special Program for Applied Science and Technology of Guangdong Province(2015B020232009,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China)Guangdong Basic and Applied Basic Research Foundation(2019A1515011256,China)Guangzhou Science and Technology Program Project(201604020121 and 201804010227,China)Yang Fan Project of Guangdong Province(Grant No.2014YT02S044,China)Guangdong Provincial Key Laboratory of Construction Foundation(No.2017B030314030,China)。
文摘The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases II(Pol II)and leading to transcription elongation.The present study identified a novel post-translational modification of BRD4:poly(ADPribosyl)ation(PARylation),that was mediated by poly(ADP-ribose)polymerase-1(PARP1)in cardiac hypertrophy.BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol(ISO),whereas overexpression of BRD4 promoted cardiac hypertrophy,confirming the critical role of BRD4 in pathological cardiac hypertrophy.PARP1 was activated in ISOinduced cardiac hypertrophy and facilitated the development of cardiac hypertrophy.BRD4 was involved in the prohypertrophic effect of PARP1,as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses,and that BRD4 overexpression suppressed the antihypertrophic effect of PARP1 inhibitors.Interactions of BRD4 and PARP1 were observed by coimmunoprecipitation and immunofluorescence.PARylation of BRD4 induced by PARP1 was investigated by PARylation assays.In response to hypertrophic stimuli like ISO,PARylation level of BRD4 was elevated,along with enhanced interactions between BRD4 and PARP1.By investigating the PARylation of truncation mutants of BRD4,the C-terminal domain(CTD)was identified as the PARylation modification sites of BRD4.PARylation of BRD4 facilitated its binding to the transcription start sites(TSS)of hypertrophic genes,resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes.The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.
基金supported by grants from the Natural Science Foundation of Guangdong Province(No. 2016A030313796/2017B030311010)
文摘Background Cardiac hypertrophy(CH)is a pathological state of heart which could lead to arrhythmias,cardiac failure,and sudden cardiac death.Pathology of cardiac hypertrophy has been acknowledged widely,but the detailed molecular mechanism has not been explored thoroughly.Our study was designed to identify differentially expressed genes(DEGs),and to explore the molecular mechanism and core genes that may be involved in the progression of cardiac hypertrophy.Methods Microarray data of cardiac hypertrophy(GSE76)was downloaded from the Gene Expression Omnibus(GEO)database.The DEGs were identified by R.Then Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis and protein-protein interaction(PPI)network analyses were performed by DAVID,STRING and Cytoscape.Results 1014 DEGs in GSE76 were identified,970 were downregulated genes and 44 were upregulated genes in cardiac hypertrophic tissues.The biological process(BP)analysis revealed that DEGs mainly included genes for inflammatory response,cell adhesion,and cell proliferation.The core genes were associated with cardiac remodeling and fibrosis,cell growth,inflammatory reaction,and cell adhesion.Conclusions This study indicated the potential significance of immune injury and cardiac fibrosis in the progression of cardiac hypertrophy.Meanwhile,the core genes may provide molecular targets for the disease diagnosis or drug treatment of cardiac hypertrophy in the future.
基金supported by the grants from National Key Research and Development Project(2018YFE0113500 to JX)National Natural Science Foundation of China(82020108002 and 81911540486 to JX,81970335 and 82170285 to YB)+4 种基金Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to JX)Science and Technology Commission of Shanghai Municipality(20DZ2255400 and 18410722200 to JX)the“Dawn”Program of Shanghai Education Commission(19SG34 to JX)the Shanghai Rising-Star Program(19QA1403900 to YB)the Science and Technology Commission of Shanghai Municipality(21SQBS00100 to YB).
文摘Background:Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart.Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes.However,it remains unclear whether and how lymphangiogenesis contributes to exercise-induced physiological cardiac growth.We aimed to investigate the role and mechanism of lymphangiogenesis in exercise-induced physiological cardiac growth.Methods:Adult C57 BL6/J mice were subjected to 3 weeks of swimming exercise to induce physiological cardiac growth.Oral treatment with vascular endothelial growth factor receptor 3(VEGFR3) inhibitor SAR1 3 1 675 was used to investigate whether cardiac lymphangiogenesis was required for exercise-induced physiological cardiac growth by VEGFR3 activation.Furthermore,human dermal lymphatic endothelial cell(LEC)-conditioned medium was collected to culture isolated neonatal rat cardiomyocytes to determine whether and how LECs could influence cardiomyocyte proliferation and hypertrophy.Results:Swimming exercise induced physiological cardiac growth accompanied by a remarkable increase of cardiac lymphangiogenesis as evidenced by increased density of lymphatic vessel endothelial hyaluronic acid receptor 1-positive lymphatic vessels in the heart and upregulated LYVE-1 and Podoplanin expressions levels.VEGFR3 was upregulated in the exercised heart,while VEGFR3 inhibitor SAR131675 attenuated exercise-induced physiological cardiac growth as evidenced by blunted myocardial hypertrophy and reduced proliferation marker Ki67 in cardiomyocytes,which was correlated with reduced lymphatic vessel density and downregulated LYVE-1 and Podoplanin in the heart upon exercise.Furthermore,LEC-conditioned medium promoted both hypertrophy and proliferation of cardiomyocytes and contained higher levels of insulinlike growth factor-1 and the extracellular protein Reelin,while LEC-conditioned medium from LECs treated with SAR131675 blocked these effects.Functional rescue assays further demonstrated that protein kinase B(AKT) activation,as well as reduced CCAAT enhancer-binding protein beta(C/EBPβ) and increased CBP/p300-interacting transactivators with E(glutamic acid)/D(aspartic acid)-rich-carboxylterminal domain 4(CITED4),contributed to the promotive effect of LEC-conditioned medium on cardiomyocyte hypertrophy and proliferation.Conclusion:Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation,and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis.These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth.
基金supported by the National Natural Science Foundation of China(No.81760058,81560059,81660042,31800891)the Scientific Research Project of Health and Family Planning Commission of Hunan Province(No.C2017025)+1 种基金the Project of Medical and Health Science and Technology of Shaoxing City(No.2020A13063)the Startup Fund for Research of Shaoxing University(No.20205021)。
文摘Free fatty acids(FFAs)play important roles in cardiovascular disease.Studies have shown that it is an important way for FAs to exert biological effects through their own receptors besides directly participating biochemical reaction in body.Free fatty acid receptor 2(FFA2)can be activated by short-chain FAs and is involved in inflammatory reactions and lipid accumulation.Since the known pathological changes caused by FFA2 are also implicated in cardiac hypertrophy,we hypothesized that FFA2 might be pathogenic in cardiac hypertrophy.This paper showed that FFA2 expression significantly increased in cardiac hypertrophy in vivo and in vitro.FFA2 agonist 4-CMTB or TUG-1375 promoted the expression of the hypertrophy markers ANF and BNP and increased cell surface area in vitro,which was further strengthened by FFA2 overexpression,suggesting that FFA2 might contribute to cardiomyocyte hypertrophy.Furthermore,4-CMTB treatment or FFA2 overexpression combined with 4-CMTB treatment elevated the phosphorylation and transcriptional activity of GATA4 and STAT3,which were inhibited by an ERK1/2 inhibitor,and GATA4 and STAT3 knockdown inhibited the elevation of hypertrophy biomarkers in cardiomyocytes treated with 4-CMTB.Taken together,these data indicate that FFA2 can enhance cardiomyocyte hypertrophy by activating STAT3 and GATA4 via ERK1/2,providing a potential new target for therapy.
基金the State Key Program of the National Natural Science Foundation of China(82030059)National Natural Science Foundation of China(82172178,82072144,81873950,81873953,81300219,81671951)+6 种基金National Key R&D Program of China(2020YFC1512700,2020YFC1512705,2020YFC1512703)National S&T Fundamental Resources Investigation Project(2018FY100600,2018FY100602)Natural Science Foundation of Shandong Province(ZR2022MH078)Key R&D Program of Shandong Province(2019GSF108131)Taishan Pandeng Scholar Program of Shandong Province(tspd20181220)Taishan Young Scholar Program of Shandong Province(tsqn202103173,tsqn20161065,tsqn201812129)Youth Top-Talent Project of National Ten Thousand Talents Plan,and Qilu Young Scholar Program.
文摘Background:Visceral adipose tissue-derived serine protease inhibitor(vaspin),a secretory adipokine,protects against insulin resistance.Recent studies have demonstrated that serum vaspin levels are decreased in patients with coronary artery disease and that vaspin protects against myocardial ischemia-reperfusion injury and atherosclerosis.However,it remains unclear whether vaspin exerts specific effects on pathological cardiac hypertrophy.Methods:An in vivo study was conducted using a cardiac hypertrophy model established by subcutaneous injection of isoproterenol(ISO)in C57BL/6 and vaspin-ko mice.Rapamycin was administered intraperitoneally to mice,for further study.H9c2 cells and neonatal rat ventricular myocytes(NRVMs)were treated with ISO to induce hypertrophy.Human vaspin fusion protein,the proteasome inhibitor MG132,and chloroquine diphosphate were used for further mechanistic studies.Results:Here,we provide the first evidence that vaspin knockdown results in markedly exaggerated cardiac hypertrophy,fibrosis,and cardiomyocyte senescence in mice treated with ISO.Conversely,the administration of exogenous recombinant human vaspin protected NRVMs in vitro against ISO-induced hypertrophy and senescence.Furthermore,vaspin significantly potentiated the ISO-induced decrease in autophagy.Both rapamycin and chloroquine diphosphate regulated autophagy in vivo and in vitro,respectively,and participated in vaspin-mediated cardioprotection.Moreover,the PI3K-AKT-mTOR pathway plays a critical role in vaspin-mediated autophagy in cardiac tissues and NRVMs.Our data showed that vaspin downregulated the p85 and p110 subunits of PI3K by linking p85 and p110 to NEDD4L-mediated ubiquitination degradation.Conclusion:Our results show,for the first time,that vaspin functions as a critical regulator that alleviates pathological cardiac hypertrophy by regulating autophagy-dependent myocardial senescence,providing potential preventive and therapeutic targets for pathological cardiac hypertrophy.
基金National Natural Science Foundation of China(No.31570949)。
文摘Objective:To investigate the effects of cagliazin,a sodium-glucose cotransporter 2 inhibitor(SGLT-2I),on ventricular remodeling in spontaneously hypertensive rats(SHR)through renin angiotensin system(RAS)and transforming growth factor-β1(TGF-β1).Methods:The experiment was divided into 4 groups:normal blood pressure control group,SHR group,cagliet net low-dose group(30mg/kg),cagliet net high-dose group(60mg/kg),once a day for 8 weeks.Normal blood pressure rats(WKY)were used as the control group to measure blood pressure with tail sleeve sphygmomanometer(BP)and blood glucose level was measured with glucose meter Cardiac function was evaluated by echocardiography,cell area of left ventricle was evaluated by histomorphology,real-time quantitative polymerase chain reaction and protein imprinting hybridization were used to detect TGF-β1 Smad4 renin from type I collagen(Col1a)type III collagen(Col3a)matrix metalloproteinase 2(MMP-2)Expression results of angiotensin II1 type receptor 1(AGTR1)and Angiotensin II2 type receptor 2(AGTR2).Results:After 8 weeks of administration,the cardiac weight/body weight ratio(HW/BW)of left ventricular weight/heart weight ratio(LVW/HW)of kaglinet low-dose group and high-dose group was statistically significant compared with that of spontaneous hypertensive rats(P<);Compared with SHRs,the expression of Col1a,Col3a,MMP2,TGF-β1,Smad4,Renin AGTR1 was significantly down-regulated and the expression of AGTR2 was up-regulated in cagliet net low-dose and high-dose groups Conclusions:Cagliazin can improve hypertension-induced cardiac remodeling by regulating RAS and TGF-β1/Smad signaling pathways.Conclusion:From the results,canaglifozin was found to ameliorate pressure overload-induced cardiac remodeling by regulating the RAS and TGF-β1/Smad signaling pathway.
基金This work is supported by National Natural Science Foundation of China(Nos.81670257,81970227 to J.Chen,and 82000244 to F.Gao)Zhejiang Provincial NSF project(LZ20H020001 to J.Chen.)China Postdoctoral Science Foundation(2020 M671751 and 2021 T140596 to F.Gao).
文摘Cardiovascular diseases are the leading cause of death worldwide. Cardiomyocytes are capable of coordinatedcontractions, which are mainly responsible for pumping blood. When cardiac stress occurs, cardiomyocytesundergo transition from physiological homeostasis to hypertrophic growth, proliferation, or apoptosis. During theseprocesses, many cellular factors and signaling pathways participate. PTEN is a ubiquitous dual-specificityphosphatase and functions by dephosphorylating target proteins or lipids, such as PIP3, a second messenger in thePI3K/AKT signaling pathway. Downregulation of PTEN expression or inhibiting its biologic activity improves heartfunction, promotes cardiomyocytes proliferation, reduces cardiac fibrosis as well as dilation, and inhibits apoptosisfollowing ischemic stress such as myocardial infarction. Inactivation of PTEN exhibits a potentially beneficialtherapeutic effects against cardiac diseases. In this review, we summarize various strategies for PTEN inactivationand highlight the roles of PTEN-less in regulating cardiomyocytes during cardiac development and stress responses.
基金supported Science and Technology Key Research Project in Jining(No.2018SMNS006)Teaching Case Library Project of 2018 Professional Degree Graduate Student in Shandong Province(No.SDYAL18100)
文摘Background Myocardial hypertrophy is an adaptive and compensatory response to pathological changes caused by circulatory overload and various factors.Myocardial hypertrophy have been a hot research topic in the field of cardiovascular medicine.The research mainly involves the mechanism of myocardial hypertrophy and the development of effective drugs to prevent or slow down myocardial hypertrophy and myocardial remodeling.A large number of studies have shown that many Chinese medicine monomers may play a role in preventing the occurrence of myocardial hypertrophy.In order to understand the perspectives and development of traditional Chinese medicine monomers in the treatment of myocardial hypertrophy,this article reviewed the mechanism of various traditional Chinese medicine monomers in the treatment of myocardial hypertrophy.[S Chin J Cardiol 2021;22(1):65-68]
