| First Author | He Q | Year | 2014 |
| Journal | Circ Heart Fail | Volume | 7 |
| Issue | 6 | Pages | 1032-41 |
| PubMed ID | 25277999 | Mgi Jnum | J:319065 |
| Mgi Id | MGI:6862577 | Doi | 10.1161/CIRCHEARTFAILURE.114.001260 |
| Citation | He Q, et al. (2014) Activation of liver-X-receptor alpha but not liver-X-receptor beta protects against myocardial ischemia/reperfusion injury. Circ Heart Fail 7(6):1032-41 |
| abstractText | BACKGROUND: Liver-X-receptors, LXRalpha (NR1H3) and LXRbeta (NR1H2), encode 2 different but highly homologous isoforms of transcription factors belonging to the nuclear receptor superfamily. Whether LXRalpha and LXRbeta 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 LXRalpha, LXRbeta, or both; and those overexpressing LXRalpha or LXRbeta by in vivo intramyocardial adenoviral vector) were subjected to MI/R injury. Both LXRalpha and LXRbeta were detected in wild-type mouse heart. LXRalpha, but not LXRbeta, was significantly upregulated after MI/R. Dual activation of LXRalpha and LXRbeta 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 LXRalpha, but not LXRbeta subtype. Moreover, LXRalpha/beta double-knockout and LXRalpha-knockout mice, but not LXRbeta-knockout mice, increased MI/R injury, exacerbated MI/R-induced oxidative/nitrative stress, and aggravated endoplasmic reticulum stress and mitochondrial dysfunction. Furthermore, cardiac LXRalpha, not LXRbeta, overexpression via adenoviral transfection suppressed MI/R injury. CONCLUSIONS: Our study provides the first direct evidence that the LXRalpha, but not LXRbeta, subtype is a novel endogenous cardiac protective receptor against MI/R injury. Drug development strategies specifically targeting LXRalpha may be beneficial in treating ischemic heart disease. |
