title: ZLN005 protects cardiomyocytes against high glucose-induced cytotoxicity by promoting SIRT1 expression and autophagy.
abstract: Diabetic cardiomyopathy increases the risk for the development of heart failure independent of coronary artery disease and hypertension. Either type 1 or type 2 diabetes is often accompanied by varying degrees of hyperglycemia, which has been proven to induce myocardial apoptosis in animal models. Recently, a novel small molecule, ZLN005, has been reported to show antidiabetic efficacy in a mouse model, possibly by induction of PGC-1α expression. In this study, we investigated whether ZLN005 protects cardiomyocytes against high glucose-induced cytotoxicity and the mechanisms involved. Neonatal mouse cardiomyocytes were incubated with media containing 5.5 or 33mM glucose for 24h in the presence or absence of ZLN005. ZLN005 treatment led to ameliorated cardiomyocyte oxidative injury, enhanced cell viability, and reduced apoptosis in the high glucose environment. Western blot analysis revealed that high glucose suppressed cardiomyocyte autophagy, whereas ZLN005 increased the expression of autophagy marker proteins ATG5, beclin1, and LC3 II/LC3 I; this increase was accompanied by increased expression of SIRT1. Furthermore, EX527, a SIRT1-specific inhibitor, weakened the protective effects of ZLN005 on cardiomyocytes subjected to high glucose. Taken together, these results suggest that ZLN005 suppresses high glucose-induced cardiomyocyte injury by promoting SIRT1 expression and autophagy.
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China.
authors.forename: Wenju
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Xiao
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China.
authors.forename: Dongbo
authors.initials: D
authors.lastname: Ou
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China.
authors.forename: Song
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, China. Electronic address: tdxznk01@163.com.
authors.forename: Qiangsun
authors.initials: Q
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D002316:Cardiotonic Agents; D012333:RNA, Messenger; C581161:ZLN005; D007770:L-Lactate Dehydrogenase; D056564:Sirtuin 1; D005947:Glucose
keywords: Autophagy; Cardiomyocyte; High glucose; SIRT1; ZLN005