title: Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis.
abstract: Cell death in MI is the most critical determinant of subsequent left ventricular remodeling and heart failure. Besides apoptosis, autophagy and necroptosis have been recently found to be another two regulated cell death styles. HGF has been reported to have a protective role in MI, but its impact on the three death styles remains unclear. Thus, our study was performed to investigate the distribution of autophagy, apoptosis and necroptosis in cardiac tissues after MI and explore the role and mechanism of Ad-HGF on cardiac remodeling by regulating the three death styles. We firstly showed the distribution of autophagy, apoptosis and necroptosis differs in temporal and spatial context after MI using immunofluorescence. Notably, Ad-HGF treatment improves the cardiac remodeling of SD rats following MI by preserving the heart function, reducing the scar size and aggresomes. Further mechanism study reveals Ad-HGF promotes autophagy and necroptosis and inhibits apoptosisin vivoandin vitro. Co-immunoprecipitation assays showed Ad-HGF treatment significantly decreased the binding of Bcl-2 to Beclin1 but enhanced Bcl-2 binding to Bax in H9c2 cells under hypoxia. Moreover, HGF-induced sequestration of Bax by Bcl-2 allows Bax to become inactive, thereby inhibiting apoptosis. In addition, Ad-HGF markedly increased the formation of Beclin1-Vps34-Atg14L complex, which accounted for promoting autophagy. Both the western blot and activity assay showed Ad-HGF significantly decreased the caspase 8 protein and activity levels, which obligated the cell to undergo necroptosis under hypoxia and block apoptosis. Thus, our findings offer new evidence and strategies for the treatment of MI and post-MI cardiac remodeling.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University Nanjing, China.
authors.forename: Jiabao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University Nanjing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University Nanjing, China.
authors.forename: Yunle
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University Nanjing, China.
authors.forename: Yingqiang
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University Nanjing, China.
authors.forename: Nan
authors.initials: N
authors.lastname: A
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University Nanjing, China.
authors.forename: Shuiyuan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University Nanjing, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University Nanjing, China.
authors.forename: Ningtian
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University Nanjing, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, China; Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Yang
keywords: Ad-HGF; apoptosis; autophagy; cardiac remodeling; myocardial infarction; necroptosis