BACKGROUND The inflammatory response caused by the NLRP3 is closely related to the formation of myocardial ischemiareperfusion injury.Costimulatory receptor CD137 and its ligand play a crucial role in regulating the i...BACKGROUND The inflammatory response caused by the NLRP3 is closely related to the formation of myocardial ischemiareperfusion injury.Costimulatory receptor CD137 and its ligand play a crucial role in regulating the inflammatory immune response in atherosclerosis,which is the fundamental cause of cardiovascular diseases.However,the roles of CD137 signaling in the process of myocardial ischaemia-reperfusion(IR)injury remain unknown.METHODS Genetic ablation was used to determine the functional significance of CD137 in myocardial IR injury.Expression of CD137 was examined by Western-blot,quantitative real-time polymerase chain reaction,and immunohistochemistry in a murine IR model by coronary artery ligation.Even’s blue-TTC staining and echocardiography to evaluate the severity of myocardial IR injury.Furthermore,HL-1 cardiomyocytes treated with agonist-CD137 recombinant protein were used to explore the underlying mechanism in CD137 signaling-induced NLRP3 inflammasome activation in response to hypoxia/reoxygenation or LPS/ATP.RESULTS We demonstrated that CD137 knockout significantly improved cardiac function,accompanied by a markedly reduced NLRP3-mediated inflammatory response and IA/AAR which were reversed by mitophagy inhibitor Mdivi-1.Activating CD137 signaling significantly inhibited mitophagy and provoked NLRP3-mediated inflammatory response in H/R-injured or LPS-primed and ATP-stimulated HL-1 cardiomyocytes,the effects of which could be abolished by either anti-CD137 or mitophagy activator FCCP.Besides,mitochondrial ROS was augmented by activating CD137 signaling through the suppression of mitophagy.CONCLUSIONS Our results reveal that activating CD137 signaling aggravates myocardial IR injury by upregulating NLRP3 inflammasome activation via suppressing mitophagy and promoting mtROS generation.展开更多
BACKGROUND Advanced glycation end products(AGEs)are diabetic metabolic toxic products that cannot be ignored.Nε-(carboxymethyl)lysine(CML),a component of AGEs,could increase macrophage lipid uptake,promote foam cell ...BACKGROUND Advanced glycation end products(AGEs)are diabetic metabolic toxic products that cannot be ignored.Nε-(carboxymethyl)lysine(CML),a component of AGEs,could increase macrophage lipid uptake,promote foam cell formation,and thereby accelerate atherosclerosis.The receptor for AGEs(RAGE)and cluster of differentiation 36(CD36)were the receptors of CML.However,it is still unknown whether RAGE and CD36 play key roles in CML-promoted lipid uptake.AIM Our study aimed to explore the role of RAGE and CD36 in CML-induced macrophage lipid uptake.METHODS In this study,we examined the effect of CML on lipid uptake by Raw264.7 macrophages.After adding 10 mmol/L CML,the lipid accumulation in macrophages was confirmed by oil red O staining.Expression changes of CD36 and RAGE were detected with immunoblotting and quantitative real-time polymerase chain reaction.The interaction between CML with CD36 and RAGE was verified by immunoprecipitation.We synthesized a novel N-succinimidyl-4-18Ffluorobenzoate-CML radioactive probe.Radioactive receptor-ligand binding assays were performed to test the binding affinity between CML with CD36 and RAGE.The effects of blocking CD36 or RAGE on CML-promoting lipid uptake were also detected.RESULTS The study revealed that CML significantly promoted lipid uptake by macrophages.Immunoprecipitation and radioactive receptor-ligand binding assays indicated that CML could specifically bind to both CD36 and RAGE.CML had a higher affinity for CD36 than RAGE.ARG82,ASN71,and THR70 were the potential interacting amino acids that CD36 binds to CML Anti-CD36 and anti-RAGE could block the uptake of CML by macrophages.The lipid uptake promotion effect of CML was significantly attenuated after blocking CD36 or RAGE.CONCLUSION Our results suggest that the binding of CML with CD36 and RAGE promotes macrophage lipid uptake.展开更多
With the high incidence of diabetes around the world,ischemic complications cause a serious influence on people’s production and living.Neovascularization plays a significant role in its development.Therefore,neovasc...With the high incidence of diabetes around the world,ischemic complications cause a serious influence on people’s production and living.Neovascularization plays a significant role in its development.Therefore,neovascularization after diabetic ischemia has aroused attention and has become a hot spot in recent years.Neovascularization is divided into angiogenesis represented by atherosclerosis and arteriogenesis characterized by coronary collateral circulation.When mononuclear macrophages successively migrate to the ischemia anoxic zone after ischemia or hypoxia,they induce the secretion of cytokines,such as vascular endothelial growth factor and hypoxia-inducible factor,activate signaling pathways such as classic Wnt and phosphatidylinositol 3 kinase(PI3K)/protein kinase B(Akt)pathways,trigger oxidative stress response,activate endothelial progenitor cells or enter the glycolysis or lactic acid process and promote the formation of new blood vessels,remodeling them into mature blood vessels and restoring blood supply.However,the hypoglycemic condition has different impacts on neovascularization.Consequently,this review aimed to introduce the mechanisms of neovascularization after diabetic ischemia,increase our understanding of diabetic ischemic complications and their therapies and provide more treatment options for clinical practice and effectively relieve patients’pain.It is believed that in the near future,neovascularization will bring more benefits and hope to patients with diabetes.展开更多
Purpose:To compare the effectiveness of the interventional limb raising management strategy(ILRMS)to elastic bandage compression at radial vascular access sites following coronary angiographies(CAGs)and percutaneous c...Purpose:To compare the effectiveness of the interventional limb raising management strategy(ILRMS)to elastic bandage compression at radial vascular access sites following coronary angiographies(CAGs)and percutaneous coronary interventions(PCIs).Methods:Patients with ischemic coronary heart disease whose condition was stable over three months were enrolled in this clinical study(n=590;aged 25e80).All participants had just undergone CAG and PCI.Patients were randomized into either the ILRMS group(n=360)or standard post-intervention care with an elastic bandage(n=230).Overall comfort and wrist pain was assessed and the degree of index finger swelling and oxygen saturation was measured on the affected arm.All variables were measured prior to postintervention treatment and again at six hours after CAG and PCI.Results:We found that patients receiving ILRMS had significantly lower wrist pain scores and swelling around the index finger compared to the elastic bandage group(p<0.05).Oxygen saturation of the index finger was not statistically significant(p>0.05).We also found that 19.57%of the elastic bandage patients were comfortable,while ILRMS patients were significantly more comfortable(93.06%;p<0.05).Conclusions:We find that ILRMS alleviates swelling and pain of the wrist more effectively than current practices and improves the degree of overall comfort of patients who undergo CAG and PCI.展开更多
BACKGROUND Myocardial remodeling is a key factor in the progression of cardiovascular disease to the end stage.In addition to myocardial infarction or stress overload,dietary factors have recently been considered asso...BACKGROUND Myocardial remodeling is a key factor in the progression of cardiovascular disease to the end stage.In addition to myocardial infarction or stress overload,dietary factors have recently been considered associated with myocardial remodeling.Nε-(carboxymethyl)lysine(CML)is a representative foodborne toxic product,which can be ingested via daily diet.Therefore,there is a marked need to explore the effects of dietary CML on the myocardium.AIM To explore the effects of dietary CML(dCML)on the heart.METHODS C57 BL/6 mice were divided into a control group and a dCML group.The control group and the dCML group were respectively fed a normal diet or diet supplemented with CML for 20 wk.Body weight and blood glucose were recorded every 4 wk.^(18)F-fluorodeoxyglucose(FDG)was used to trace the glucose uptake in mouse myocardium,followed by visualizing with micro-positron emission tomography(PET).Myocardial remodeling and glucose metabolism were also detected.In vitro,H9C2 cardiomyocytes were added to exogenous CML and cultured for 24 h.The effects of exogenous CML on glucose metabolism,collagen I expression,hypertrophy,and apoptosis of cardiomyocytes were analyzed.RESULTS Our results suggest that the levels of fasting blood glucose,fasting insulin,and serum CML were significantly increased after 20 wk of dCML.Micro-PET showed that ^(18)F-FDG accumulated more in the myocardium of the dCML group than in the control group.Histological staining revealed that dCML could lead to myocardial fibrosis and hypertrophy.The indexes of myocardial fibrosis,apoptosis,and hypertrophy were also increased in the dCML group,whereas the activities of glucose metabolism-related pathways and citrate synthase(CS)were significantly inhibited.In cardiomyocytes,collagen I expression and cellular size were significantly increased after the addition of exogenous CML.CML significantly promoted cellular hypertrophy and apoptosis,while pathways involved in glucose metabolism and level of Cs mRNA were significantly inhibited.CONCLUSION This study reveals that dCML alters myocardial glucose metabolism and promotes myocardial remodeling.展开更多
基金supported as follows:National Natural Science Foundation of China(81970379)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_3712)Medical Innovation Team Project of Jiangsu Province(CXTDA2017010).
文摘BACKGROUND The inflammatory response caused by the NLRP3 is closely related to the formation of myocardial ischemiareperfusion injury.Costimulatory receptor CD137 and its ligand play a crucial role in regulating the inflammatory immune response in atherosclerosis,which is the fundamental cause of cardiovascular diseases.However,the roles of CD137 signaling in the process of myocardial ischaemia-reperfusion(IR)injury remain unknown.METHODS Genetic ablation was used to determine the functional significance of CD137 in myocardial IR injury.Expression of CD137 was examined by Western-blot,quantitative real-time polymerase chain reaction,and immunohistochemistry in a murine IR model by coronary artery ligation.Even’s blue-TTC staining and echocardiography to evaluate the severity of myocardial IR injury.Furthermore,HL-1 cardiomyocytes treated with agonist-CD137 recombinant protein were used to explore the underlying mechanism in CD137 signaling-induced NLRP3 inflammasome activation in response to hypoxia/reoxygenation or LPS/ATP.RESULTS We demonstrated that CD137 knockout significantly improved cardiac function,accompanied by a markedly reduced NLRP3-mediated inflammatory response and IA/AAR which were reversed by mitophagy inhibitor Mdivi-1.Activating CD137 signaling significantly inhibited mitophagy and provoked NLRP3-mediated inflammatory response in H/R-injured or LPS-primed and ATP-stimulated HL-1 cardiomyocytes,the effects of which could be abolished by either anti-CD137 or mitophagy activator FCCP.Besides,mitochondrial ROS was augmented by activating CD137 signaling through the suppression of mitophagy.CONCLUSIONS Our results reveal that activating CD137 signaling aggravates myocardial IR injury by upregulating NLRP3 inflammasome activation via suppressing mitophagy and promoting mtROS generation.
基金Supported by The National Natural Science Foundation of China,No.82070455Natural Science Foundation of Jiangsu Province,No.BK20201225Medical Innovation Team Project of Jiangsu Province,No.CXTDA2017010。
文摘BACKGROUND Advanced glycation end products(AGEs)are diabetic metabolic toxic products that cannot be ignored.Nε-(carboxymethyl)lysine(CML),a component of AGEs,could increase macrophage lipid uptake,promote foam cell formation,and thereby accelerate atherosclerosis.The receptor for AGEs(RAGE)and cluster of differentiation 36(CD36)were the receptors of CML.However,it is still unknown whether RAGE and CD36 play key roles in CML-promoted lipid uptake.AIM Our study aimed to explore the role of RAGE and CD36 in CML-induced macrophage lipid uptake.METHODS In this study,we examined the effect of CML on lipid uptake by Raw264.7 macrophages.After adding 10 mmol/L CML,the lipid accumulation in macrophages was confirmed by oil red O staining.Expression changes of CD36 and RAGE were detected with immunoblotting and quantitative real-time polymerase chain reaction.The interaction between CML with CD36 and RAGE was verified by immunoprecipitation.We synthesized a novel N-succinimidyl-4-18Ffluorobenzoate-CML radioactive probe.Radioactive receptor-ligand binding assays were performed to test the binding affinity between CML with CD36 and RAGE.The effects of blocking CD36 or RAGE on CML-promoting lipid uptake were also detected.RESULTS The study revealed that CML significantly promoted lipid uptake by macrophages.Immunoprecipitation and radioactive receptor-ligand binding assays indicated that CML could specifically bind to both CD36 and RAGE.CML had a higher affinity for CD36 than RAGE.ARG82,ASN71,and THR70 were the potential interacting amino acids that CD36 binds to CML Anti-CD36 and anti-RAGE could block the uptake of CML by macrophages.The lipid uptake promotion effect of CML was significantly attenuated after blocking CD36 or RAGE.CONCLUSION Our results suggest that the binding of CML with CD36 and RAGE promotes macrophage lipid uptake.
基金Supported by the National Natural Science Foundation of China,No.82070455the Related Foundation of Jiangsu Province,No.BK20201225+1 种基金the Medical Innovation Team Project of Jiangsu Province,No.CXTDA2017010the Postgraduate Research and Practice Innovation Program of Jiangsu Province,No.KYCX20_3051.
文摘With the high incidence of diabetes around the world,ischemic complications cause a serious influence on people’s production and living.Neovascularization plays a significant role in its development.Therefore,neovascularization after diabetic ischemia has aroused attention and has become a hot spot in recent years.Neovascularization is divided into angiogenesis represented by atherosclerosis and arteriogenesis characterized by coronary collateral circulation.When mononuclear macrophages successively migrate to the ischemia anoxic zone after ischemia or hypoxia,they induce the secretion of cytokines,such as vascular endothelial growth factor and hypoxia-inducible factor,activate signaling pathways such as classic Wnt and phosphatidylinositol 3 kinase(PI3K)/protein kinase B(Akt)pathways,trigger oxidative stress response,activate endothelial progenitor cells or enter the glycolysis or lactic acid process and promote the formation of new blood vessels,remodeling them into mature blood vessels and restoring blood supply.However,the hypoglycemic condition has different impacts on neovascularization.Consequently,this review aimed to introduce the mechanisms of neovascularization after diabetic ischemia,increase our understanding of diabetic ischemic complications and their therapies and provide more treatment options for clinical practice and effectively relieve patients’pain.It is believed that in the near future,neovascularization will bring more benefits and hope to patients with diabetes.
基金This work was supported by the National Natural Science Foundation of China(GrantNos.81170279,81370408,81370409)the Social Development Projects of Jiangsu Province(WS074,LJ201116,Q201308)the Projects from Social Development of Zhenjiang(SS2012002,SH2013023,SH2013024).
文摘Purpose:To compare the effectiveness of the interventional limb raising management strategy(ILRMS)to elastic bandage compression at radial vascular access sites following coronary angiographies(CAGs)and percutaneous coronary interventions(PCIs).Methods:Patients with ischemic coronary heart disease whose condition was stable over three months were enrolled in this clinical study(n=590;aged 25e80).All participants had just undergone CAG and PCI.Patients were randomized into either the ILRMS group(n=360)or standard post-intervention care with an elastic bandage(n=230).Overall comfort and wrist pain was assessed and the degree of index finger swelling and oxygen saturation was measured on the affected arm.All variables were measured prior to postintervention treatment and again at six hours after CAG and PCI.Results:We found that patients receiving ILRMS had significantly lower wrist pain scores and swelling around the index finger compared to the elastic bandage group(p<0.05).Oxygen saturation of the index finger was not statistically significant(p>0.05).We also found that 19.57%of the elastic bandage patients were comfortable,while ILRMS patients were significantly more comfortable(93.06%;p<0.05).Conclusions:We find that ILRMS alleviates swelling and pain of the wrist more effectively than current practices and improves the degree of overall comfort of patients who undergo CAG and PCI.
基金Supported by the National Natural Science Foundation of China,No.82070455Natural Science Foundation of Jiangsu Province,No.BK20201225+1 种基金Medical Innovation Team Project of Jiangsu Province,No.CXTDA2017010Research and Innovation Funding Project for College Students in Experimental Animal Center of Jiangsu University。
文摘BACKGROUND Myocardial remodeling is a key factor in the progression of cardiovascular disease to the end stage.In addition to myocardial infarction or stress overload,dietary factors have recently been considered associated with myocardial remodeling.Nε-(carboxymethyl)lysine(CML)is a representative foodborne toxic product,which can be ingested via daily diet.Therefore,there is a marked need to explore the effects of dietary CML on the myocardium.AIM To explore the effects of dietary CML(dCML)on the heart.METHODS C57 BL/6 mice were divided into a control group and a dCML group.The control group and the dCML group were respectively fed a normal diet or diet supplemented with CML for 20 wk.Body weight and blood glucose were recorded every 4 wk.^(18)F-fluorodeoxyglucose(FDG)was used to trace the glucose uptake in mouse myocardium,followed by visualizing with micro-positron emission tomography(PET).Myocardial remodeling and glucose metabolism were also detected.In vitro,H9C2 cardiomyocytes were added to exogenous CML and cultured for 24 h.The effects of exogenous CML on glucose metabolism,collagen I expression,hypertrophy,and apoptosis of cardiomyocytes were analyzed.RESULTS Our results suggest that the levels of fasting blood glucose,fasting insulin,and serum CML were significantly increased after 20 wk of dCML.Micro-PET showed that ^(18)F-FDG accumulated more in the myocardium of the dCML group than in the control group.Histological staining revealed that dCML could lead to myocardial fibrosis and hypertrophy.The indexes of myocardial fibrosis,apoptosis,and hypertrophy were also increased in the dCML group,whereas the activities of glucose metabolism-related pathways and citrate synthase(CS)were significantly inhibited.In cardiomyocytes,collagen I expression and cellular size were significantly increased after the addition of exogenous CML.CML significantly promoted cellular hypertrophy and apoptosis,while pathways involved in glucose metabolism and level of Cs mRNA were significantly inhibited.CONCLUSION This study reveals that dCML alters myocardial glucose metabolism and promotes myocardial remodeling.
