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Activation of liver-X-receptor ? but not liver-X-receptor ? protects against myocardial ischemia/reperfusion injury.


ABSTRACT: Liver-X-receptors, LXR? (NR1H3) and LXR? (NR1H2), encode 2 different but highly homologous isoforms of transcription factors belonging to the nuclear receptor superfamily. Whether LXR? and LXR? 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.Mice (wild type; those genetically depleted of LXR?, LXR?, or both; and those overexpressing LXR? or LXR? by in vivo intramyocardial adenoviral vector) were subjected to MI/R injury. Both LXR? and LXR? were detected in wild-type mouse heart. LXR?, but not LXR?, was significantly upregulated after MI/R. Dual activation of LXR? and LXR? 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?, but not LXR? subtype. Moreover, LXR?/? double-knockout and LXR?-knockout mice, but not LXR?-knockout mice, increased MI/R injury, exacerbated MI/R-induced oxidative/nitrative stress, and aggravated endoplasmic reticulum stress and mitochondrial dysfunction. Furthermore, cardiac LXR?, not LXR?, overexpression via adenoviral transfection suppressed MI/R injury.Our study provides the first direct evidence that the LXR?, but not LXR?, subtype is a novel endogenous cardiac protective receptor against MI/R injury. Drug development strategies specifically targeting LXR? may be beneficial in treating ischemic heart disease.

PROVIDER: S-EPMC4527689 | BioStudies |

REPOSITORIES: biostudies

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