Abstract 9571: Activation of LXRα but Not LXRβ Protects the Heart from Ischemia/Reperfusion Injury
Objective: Liver X receptors (LXRs) play a critical regulatory role in metabolism and inflammation, and have been demonstrated to be involved in vascular physiology/pathology. However, LXR function in cardiac biology remains largely unknown. Importantly, no data exists concerning the role of LXRs in myocardial ischemia/reperfusion (MI/R) injury.
Methods and Results: Two LXR isoforms, LXRα (NR1H3) and LXRβ (NR1H2), were detected in the mouse heart. Exposure to MI/R resulted in upregulated LXRα expression in ischemic/reperfused myocardium, whereas LXRβ expression remained largely unaffected. LXR activation by natural and synthetic agonists reduced myocardial infarction and improved contractile function following MI/R injury. The cardioprotective effects of LXR agonists were completely abrogated by knock-down of endogenous cardiac LXRα, but not LXRβ, via in vivo intramyocardial siRNA transfection. LXRα knock-out mice manifested exacerbated apoptosis and infarct size with poorer contractile function post-MI/R compared to WT mice, whereas MI/R injury was similar between LXRβ knock-out and WT mice. Mechanistically, LXR agonists inhibited both endoplasmic reticulum stress (as evidenced by decreased activation of CCAAT/enhancer-binding protein homologous protein and caspase-12) and mitochondrial dysregulation (as evidenced by decreased release of mitochondrial cytochrome c and attenuated caspases-9 activation), and subsequently reduced cardiomyocyte apoptosis. Furthermore, LXR activation inhibited MI/R-induced oxidative stress (i.e., superoxide production and NADPH oxidase expression) and nitrative stress (i.e., peroxynitrite formation and inducible nitric oxide synthase expression) in ischemic/reperfused myocardium.
Conclusion: Our study provides the first evidence supporting LXRα as a novel cardiac protective receptor against MI/R injury via inhibition of both endoplasmic reticular stress and the mitochondrial apoptotic pathway. LXRα may potentially be an attractive molecular target for the treatment of ischemic heart disease.
- © 2012 by American Heart Association, Inc.