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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.

SUBMITTER: He Q

PROVIDER: S-EPMC4527689 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

He Qing Q Pu Jun J Yuan Ancai A Lau Wayne Bond WB Gao Erhe E Koch Walter J WJ Ma Xin-Liang XL He Ben B

Circulation. Heart failure 20141002 6

<h4>Background</h4>Liver-X-receptors, LXRα (NR1H3) and LXRβ (NR1H2), encode 2 different but highly homologous isoforms of transcription factors belonging to the nuclear receptor superfamily. Whether LXRα and LXRβ 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.<h4>Methods and results</h4>Mice (wild type; those genetically depleted of LXRα, LXRβ, or both; and those ...[more]

PMID: 25277999

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Project description:Mitochondrial Ca2+ overload is a main contributor to mitochondrial damage hence cardiomyocyte death in myocardial ischemia/reperfusion (MI/R) injury. MICU1 has been recently identified as an important regulator of mitochondrial Ca2+ homeostasis. Here we try to identify the role of MICU1 in MI/R, and to investigate whether the mitochondrial importer receptor Tom70 possesses critical roles in the mitochondrial translocation of MICU1 and MI/R. Specific small interfering RNA (20 μg) against MICU1 and Tom70, and lentivirus vectors carrying the Tom70a sequences (3.3 × 107 TU) were delivered through intramyocardial injection. Seventy-two hours after injection, mice were subjected to 30 min of MI followed by 3 h (for cell apoptosis and mitochondrial damage assessment) or 24 h (for cardiac function and infarct size determination) of reperfusion. MI/R had no significant effect on total MICU1 expression, but caused significant reduction of MICU1 in mitochondria. Knockdown of MICU1 significantly aggravated MI/R injury, as evidenced by enlarged infarct size, depressed cardiac function and increased myocardial apoptosis. Moreover, MICU1 deficiency resulted in markedly aggravated mitochondrial Ca2+ overload, consequently destructed mitochondrial morphology and suppressed mitochondrial function (evidenced by decreased ATP production). Interestingly, mitochondrial Tom70 was also decreased in MI/R. Genetic loss-function study revealed that mitochondrial MICU1 expression was depressed by Tom70 ablation. Furthermore, Tom70 deficiency significantly aggravated MI/R injury and worsened mitochondrial Ca2+ overload. However, supplementation of Tom70 significantly attenuated MI/R injury, preserved mitochondrial morphology and function, and inhibited mitochondrial Ca2+ overload, all of which were abolished by MICU1 suppression. Mitochondrial Tom70/MICU1 pathway protects against MI/R injury, in which mitochondrial localization of MICU1 is governed by Tom70, and MICU1 serves as an indispensable factor in Tom70's cardioprotection.

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Dataset Information

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

Publications

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

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