title: Vitamin D receptor activation protects against myocardial reperfusion injury through inhibition of apoptosis and modulation of autophagy.
abstract: OBJECTIVE
  To determine the roles of vitamin D receptor (VDR) in ischemia/reperfusion-induced myocardial injury and to investigate the underlying mechanisms involved.
  
  
  RESULTS
  The endogenous VDR expression was detected in the mouse heart, and myocardial ischemia/reperfusion (MI/R) upregulated VDR expression. Activation of VDR by natural and synthetic agonists reduced myocardial infarct size and improved cardiac function. Mechanistically, VDR activation inhibited endoplasmic reticulum (ER) stress (determined by the reduction of CCAAT/enhancer-binding protein homologous protein expression and caspase-12 activation), attenuated mitochondrial impairment (determined by the decrease of mitochondrial cytochrome c release and caspase-9 activation), and reduced cardiomyocyte apoptosis. Furthermore, VDR activation significantly inhibited MI/R-induced autophagy dysfunction (determined by the inhibition of Beclin 1 over-activation, the reduction of autophagosomes, the LC3-II/LC3-I ratio, p62 protein abundance, and the restoration of autophagy flux). Moreover, VDR activation inhibited MI/R-induced oxidative stress through a metallothionein-dependent mechanism. The cardioprotective effects of VDR agonists mentioned earlier were impaired in the setting of cardiac-specific VDR silencing. In contrast, adenovirus-mediated cardiac VDR overexpression decreased myocardial infarct size and improved cardiac function through attenuating oxidative stress, and inhibiting apoptosis and autophagy dysfunction.
  
  
  CONCLUSIONS
  Our data demonstrate that VDR is a novel endogenous self-defensive and cardioprotective receptor against MI/R injury, via mechanisms (at least in part) reducing oxidative stress, and inhibiting apoptosis and autophagy dysfunction-mediated cell death.
authors.affiliation: 1 Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China .
authors.forename: Tianbao
authors.initials: T
authors.lastname: Yao
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Ying
authors.forename: Yichao
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ancai
authors.initials: A
authors.lastname: Yuan
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.forename: Huan
authors.initials: H
authors.lastname: Tong
authors.forename: Song
authors.initials: S
authors.lastname: Ding
authors.forename: Junling
authors.initials: J
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Peng
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Pu
authors.forename: Ben
authors.initials: B
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism*
chemical_list: D018167:Receptors, Calcitriol