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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:Background: Guanxin Danshen formulation (GXDSF) is a traditional Chinese herbal recipe recorded in the Chinese Pharmacopeia since 1995 edition, which consists of Salviae miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma and Dalbergiae odoriferae Lignum. Our previous research suggested GXDSF had positive effect on cardiovascular disease. Therefore, the aim of this study was to elucidate the effects of GXDSF on myocardial ischemia reperfusion injury-induced left ventricular remodelling (MIRI-LVR). Methods: The effects of GXDSF on cardiac function were detected by haemodynamics and echocardiograms. The effects of GXDSF on biochemical parameters (AST, LDH and CK-MB) were analyzed. Histopathologic examinations were performed to evaluate the effect of GXDSF on cardiac structure. In addition, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to predict the main target of GXDSF. Target validation was conducted by using western blots and immunofluorescent double staining assays. Results: We found that +dp/dt and LVSP were significantly elevated in the GXDSF-treated groups compared with the MIRI-LVR model group. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were increased in the GXDSF-treated groups compared with the model group. All biochemical parameters (AST, LDH and CK-MB) were considerably decreased in the GXDSF-treated groups compared with the model group. Fibrosis parameters (collagen I and III, α-SMA, and left ventricular fibrosis percentage) were decreased to different degrees in the GXDSF-treated groups compared with the model group, and the collagen III/I ratio was elevated by the same treatments. TCMSP database prediction and western blot results indicated that estrogen receptor β (ERβ) could be the main target of GXDSF. PHTPP, a selective antagonist of ERβ, could inhibit the expression of ERβ and the phosphorylation of PI3K and Akt in myocardial tissue induced by GXDSF, and partly normalize the improving effects of GXDSF on +dp/dt, LVEF, LVFS, LDH, CK-MB, α-SMA and myocardial fibrosis. Conclusion: Collectively, GXDSF showed therapeutic potential for use in the prevention and treatment of myocardial ischemia reperfusion injury-induced ventricular remodeling by upregulating ERβ via PI3K/Akt signaling. Moreover, these findings may be valuable in understand the mechanism of disease and provide a potential therapy of MIRI-IVR.

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??g) 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.

Project description:Background:Oxidative stress is a major contributor to the onset and development of myocardial ischemia reperfusion injury (MIRI). Sappanone A (SA), a homoisoflavanone extracted from the heartwood of Caesalpinia sappan L., has been demonstrated to possess powerful antioxidant activity. Therefore, this study aimed to determine the protective effect of SA on MIRI and investigate its underlying mechanism. Methods:The rat hearts were isolated and underwent 30-min ischemia, followed by 120-min reperfusion to establish the MIRI model, using the Langendorff method. SA was administrated intraperitoneally into rats 1 h prior to heart isolation. The myocardial infarct size and apoptosis were measured by TTC and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Myocardial enzyme activity, MDA content and the activities of SOD and GSH-Px were detected by colorimetric spectrophotometric method. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The change in Keap1/Nrf2 signaling pathway was evaluated by Western blotting. Results:SA reduced myocardial infarct size and the release of CK-MB and LDH in a dose-dependent manner. Moreover, SA improved the recovery of cardiac function, inhibited MIRI-induced apoptosis, repressed the production of ROS and MDA, and enhanced the activities of SOD and GSH-Px. Mechanistically, SA downregulated Keap1, induced Nrf2 nuclear accumulation, and enhanced Nrf2 transcriptional activity, subsequently resulting in an increase in the expression of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1. Moreover, SA enhanced the phosphorylation of Nfr2, but the enhancement in Nfr2 phosphorylation was abrogated by PKC or PI3K inhibitor. Conclusion:Collectively, it was demonstrated that SA prevents MIRI via coordinating the cellular antioxidant defenses and maintaining the redox balance, by modulation of Nrf2 via the PKC or PI3K pathway. Therefore, SA was a potential therapeutic drug for treating MIRI.

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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