BACKGROUND Recent studies have shown that liraglutide,a glucagon-like peptide-1 receptor agonist,has unexpected cardioprotective effects.However,the distinctive effects of liraglutide on diabetic cardiomyopathy(DCM),p...BACKGROUND Recent studies have shown that liraglutide,a glucagon-like peptide-1 receptor agonist,has unexpected cardioprotective effects.However,the distinctive effects of liraglutide on diabetic cardiomyopathy(DCM),particularly its effect on mitophagy,have not been fully elucidated.AIM To investigate the effects of liraglutide on cardiac damage and mitophagy in DCM rats.METHODS A high-fat diet and streptozotocin were used to induce DCM in rats.After 12 weeks of liraglutide treatment,rats underwent assessments of cardiac function,serum biochemical parameters,histological changes,apoptosis index,and protein levels.Furthermore,neonatal rat cardiomyocytes(NRCMs)were exposed to 25 mmol/L glucose plus 250μmol/L palmitate(high glucose+palmitic acid),with or without 200 nmol/L liraglutide,to investigate the effects of liraglutide on cardiomyocyte injury and the underlying mechanisms.RESULTS Liraglutide improved myocardial function and ameliorated cardiac damage in DCM rats,as indicated by reduced myocardial apoptosis,hypertrophy,and interstitial fibrosis(P<0.05).In NRCMs,Liraglutide alleviated mitochondrial morphological and functional damage as well as oxidative stress,improved mitophagic defects,and reduced cell apoptosis(P<0.05).Mechanistically,liraglutide alleviated NRCMs damage by enhancing mitophagy mediated by the adenosine monophosphate-activated protein kinase(AMPK)-Parkin signaling pathway,which was evidenced by the reversal of its effects upon compound C treatment.CONCLUSION Liraglutide exerted cardioprotective effects in DCM rats by inhibiting cardiomyocyte apoptosis and promoting mitophagy mediated by the AMPK-Parkin signaling pathway.展开更多
Pannexin 1(Panx 1),as a large-pore membrane channel,is highly permeable to ATP and other signaling molecules.Previous studies have demonstrated the expression of Panx 1 in the nervous system,including astrocytes,micro...Pannexin 1(Panx 1),as a large-pore membrane channel,is highly permeable to ATP and other signaling molecules.Previous studies have demonstrated the expression of Panx 1 in the nervous system,including astrocytes,microglia,and neurons.However,the distribution and function of Panx 1 in the peripheral nervous system are not clear.Blocking the function of Panx 1 pharmacologically(carbenoxolone and probenecid)or with small interfering RNA targeting pannexins can greatly reduce hypotonicity-induced ATP release.Treatment of Schwann cells with a Ras homolog family member(Rho)GTPase inhibitor and small interfering RNA targeting Rho or cytoskeleton disrupting agents,such as nocodazole or cytochalasin D,revealed that hypotonicity-induced ATP release depended on intracellular RhoA and the cytoskeleton.These findings suggest that Panx 1 participates in ATP release in Schwann cells by regulating RhoA and the cytoskeleton arrangement.This study was approved by the Animal Ethics Committee of Nantong University,China(No.S20180806-002)on August 5,2018.展开更多
基金Supported by National Natural Science Foundation of China,No.81370221 and No.82172334PUMC Youth Fund,No.3332018200+1 种基金National Science and Technology Major Project of the Ministry of Science and Technology of China,No.2024ZD0522005CAMS Innovation Fund for Medical Science,No.2016-CXGC05-4 and No.2021-I2M-1-008.
文摘BACKGROUND Recent studies have shown that liraglutide,a glucagon-like peptide-1 receptor agonist,has unexpected cardioprotective effects.However,the distinctive effects of liraglutide on diabetic cardiomyopathy(DCM),particularly its effect on mitophagy,have not been fully elucidated.AIM To investigate the effects of liraglutide on cardiac damage and mitophagy in DCM rats.METHODS A high-fat diet and streptozotocin were used to induce DCM in rats.After 12 weeks of liraglutide treatment,rats underwent assessments of cardiac function,serum biochemical parameters,histological changes,apoptosis index,and protein levels.Furthermore,neonatal rat cardiomyocytes(NRCMs)were exposed to 25 mmol/L glucose plus 250μmol/L palmitate(high glucose+palmitic acid),with or without 200 nmol/L liraglutide,to investigate the effects of liraglutide on cardiomyocyte injury and the underlying mechanisms.RESULTS Liraglutide improved myocardial function and ameliorated cardiac damage in DCM rats,as indicated by reduced myocardial apoptosis,hypertrophy,and interstitial fibrosis(P<0.05).In NRCMs,Liraglutide alleviated mitochondrial morphological and functional damage as well as oxidative stress,improved mitophagic defects,and reduced cell apoptosis(P<0.05).Mechanistically,liraglutide alleviated NRCMs damage by enhancing mitophagy mediated by the adenosine monophosphate-activated protein kinase(AMPK)-Parkin signaling pathway,which was evidenced by the reversal of its effects upon compound C treatment.CONCLUSION Liraglutide exerted cardioprotective effects in DCM rats by inhibiting cardiomyocyte apoptosis and promoting mitophagy mediated by the AMPK-Parkin signaling pathway.
基金This study was supported by the National Natural Science Foundation of China,Nos.31900718(to ZYW),31872773(to GC)the National Key Research and Development Program of China,No.2017YFA0104704(to GC)+2 种基金Basic Research Program of the Education Department of Jiangsu Province of China,Nos.19KJB180024(to ZYW),18KJB180020(to WXS)Postdoctoral Science Foundation of China,No.2019M651925(to ZYW),Jiangsu Students’Platform for Innovation and Entrepreneurship Training Program of China,No.201810304031Z(to YJD)Six Talent Peaks Project in Jiangsu Province of China,No.WSN-007(to WXS).
文摘Pannexin 1(Panx 1),as a large-pore membrane channel,is highly permeable to ATP and other signaling molecules.Previous studies have demonstrated the expression of Panx 1 in the nervous system,including astrocytes,microglia,and neurons.However,the distribution and function of Panx 1 in the peripheral nervous system are not clear.Blocking the function of Panx 1 pharmacologically(carbenoxolone and probenecid)or with small interfering RNA targeting pannexins can greatly reduce hypotonicity-induced ATP release.Treatment of Schwann cells with a Ras homolog family member(Rho)GTPase inhibitor and small interfering RNA targeting Rho or cytoskeleton disrupting agents,such as nocodazole or cytochalasin D,revealed that hypotonicity-induced ATP release depended on intracellular RhoA and the cytoskeleton.These findings suggest that Panx 1 participates in ATP release in Schwann cells by regulating RhoA and the cytoskeleton arrangement.This study was approved by the Animal Ethics Committee of Nantong University,China(No.S20180806-002)on August 5,2018.
