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摘要
Background-Liver-X-receptors, LXR alpha (NR1H3) and LXR beta (NR1H2), encode 2 different but highly homologous isoforms of transcription factors belonging to the nuclear receptor superfamily. Whether LXR alpha and LXR beta subtypes have discrete roles in the regulation of cardiac physiology/pathology is unknown. We determine the role of each LXR subtype in myocardial ischemia/reperfusion (MI/R) injury. @@@ Methods and Results-Mice (wild type; those genetically depleted of LXR alpha, LXR beta, or both; and those overexpressing LXR alpha or LXR beta by in vivo intramyocardial adenoviral vector) were subjected to MI/R injury. Both LXR alpha and LXR beta were detected in wild-type mouse heart. LXR alpha, but not LXR beta, was significantly upregulated after MI/R. Dual activation of LXR alpha and LXR beta by natural and synthetic agonists reduced myocardial infarction and improved contractile function after MI/R. Mechanistically, LXR activation inhibited MI/R-induced oxidative stress and nitrative stress, attenuated endoplasmic reticulum stress and mitochondrial dysfunction, and reduced cardiomyocyte apoptosis in ischemic/reperfused myocardium. The aforementioned cardioprotective effects of LXR agonists were impaired in the setting of cardiac-specific gene silencing of LXR alpha, but not LXR beta subtype. Moreover, LXR alpha/beta double-knockout and LXR alpha-knockout mice, but not LXR beta-knockout mice, increased MI/R injury, exacerbated MI/R-induced oxidative/nitrative stress, and aggravated endoplasmic reticulum stress and mitochondrial dysfunction. Furthermore, cardiac LXR alpha, not LXR beta, overexpression via adenoviral transfection suppressed MI/R injury. @@@ Conclusions-Our study provides the first direct evidence that the LXR alpha, but not LXR beta, subtype is a novel endogenous cardiac protective receptor against MI/R injury. Drug development strategies specifically targeting LXR alpha may be beneficial in treating ischemic heart disease.
- 出版日期2014-11
- 单位上海交通大学
