Vitamin D Receptor Activation Protects Against Myocardial Reperfusion Injury Through Inhibition of Apoptosis and Modulation of Autophagy

Abstract

Aims: 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/Rinduced 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. Innovation and Conclusion: 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. Antioxid. Redox Signal. 22,[633][634][635][636][637][638][639][640][641][642][643][644][645][646][647][648][649][650]

Knockdown of lncRNA AK139328 alleviates myocardial ischaemia/reperfusion injury in diabetic mice via modulating miR‐204‐3p and inhibiting autophagy

“…Ma et al emphasized ALDH2 as therapeutic target for MIRI and it prompting autophagy during ischaemia and remained elevated autophagy at reperfusion 20. Yao et al argued the MIRI preventive role of vitamin D receptor in that its overexpression repressed abnormal apoptosis and autophagy 21. Our work figured out that knockdown of lncRNA AK139328 relieved the damage of I/R to myocardium tissue and reduced infarction size.…”

Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling

“…First, a compensatory response may occur in pathological remodeling. Similar to other negative cardiac regulators, 25,26 USP18 may increase to play a Figure 6. Transforming growth factor-β-activated kinase 1 (TAK1) blockade reverses the cardiac abnormalities in ubiquitin-specific protease 18-knockout (USP18-KO) mice after aortic banding (AB).…”

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…VDR has also been reported to regulate a variety of metabolic pathways, such as those involved in kidney diseases, immune responses and cancers. Moreover, recent evidence has demonstrated that VDR has a protective role in cardiac hypertrophy [152] , heart failure after cardiac remodeling [153] and MI/R injury [154] . LXRs have two receptor subtypes-LXRα (NR1H3) and LXRβ (NR1H2)-that exhibit different expression patterns and perform different functions [155] .…”

“…Calcitriol and paricalcitol (PC) are natural or synthetic agonists of VDR that are used to treat kidney diseases clinically. Recently, Yao et al [154] reported that calcitriol and PC activate VDR to protect against MI/R injury by reducing ERS-induced apoptosis via inhibition of caspase 12 and CHOP expression in mice. 22(R)- [156] demonstrated that 22(R)-HC and GW3965 activated LXRα, but not the LXRβ subtype, to reduce myocardial infarction and improve contractile function after MI/R by attenuating ERS and the ERSmediated apoptosis pathway by inhibiting caspase 12 and CHOP expression.…”