The nuclear melatonin receptor RORα is a novel endogenous defender against myocardial ischemia/reperfusion injury

Abstract

Circadian rhythm disruption or decrease in levels of circadian hormones such as melatonin increases ischemic heart disease risk. The nuclear melatonin receptors RORs are pivotally involved in circadian rhythm regulation and melatonin effects mediation. However, the functional roles of RORs in the heart have never been investigated and were therefore the subject of this study on myocardial ischemia/reperfusion (MI/R) injury pathogenesis. RORα and RORγ subtypes were detected in the adult mouse heart, and RORα but not RORγ was downregulated after MI/R. To determine the pathological consequence of MI/R-induced reduction of RORα, we subjected RORα-deficient staggerer mice and wild-type (WT) littermates to MI/R injury, resulting in significantly increased myocardial infarct size, myocardial apoptosis and exacerbated contractile dysfunction in the former. Mechanistically, RORα deficiency promoted MI/R-induced endoplasmic reticulum stress, mitochondrial impairments, and autophagy dysfunction. Moreover, RORα deficiency augmented MI/R-induced oxidative/nitrative stress. Given the emerging evidence of RORα as an essential melatonin effects mediator, we further investigated the RORα roles in melatonin-exerted cardioprotection, in particular against MI/R injury, which was significantly attenuated in RORα-deficient mice, but negligibly affected by cardiac-specific silencing of RORγ. Finally, to determine cell type-specific effects of RORα, we generated mice with cardiomyocyte-specific RORα overexpression and they were less vulnerable to MI/R injury. In summary, our study provides the first direct evidence that the nuclear melatonin receptor RORα is a novel endogenous protective receptor against MI/R injury and an important mediator of melatonin-exerted cardioprotection; melatonin-RORα axis signaling thus appears important in protection against ischemic heart injury.

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

“…By contrast, Mdivi1 and SP600125 treatment had the opposite effects as Yap deletion. These results indicated an important role for Yap in modulating EMT via the NK/Drp1/fission axis [45]. …”

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

“…All the studies involving human samples were approved by the Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao tong University, and conformed to the principles outlined in the Declaration of Helsinki. An expanded Materials and Methods section is available in the online-only Data Supplement, which includes detailed information on the following aspects: generation of global USP4 knockout and USP4 transgenic mice, surgical procedure of AB, 21 histological analysis, echocardiographic measurement, 22 culture of neonatal rat ventricular myocytes and adenovirus transfection, 23,24 immunofluorescence analysis, 25,26 ubiquitination assay, 27 immunoprecipitation, Western blot and quantitative real-time polymerase chain reaction, and human heart samples.…”

Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling

“…CAG-CAT-USP18 TG mice was produced by microinjecting this construct into fertilized C57BL/6J mouse embryos. 17 To induce USP18 expression specifically in the heart, CAG-CAT-USP18 TG mice were bred with mice that carried the Cre gene under the control of the cardiac-specific α-myosin heavy chain (α-MHC) promoter. Cardiac-specific expression of the USP18 was induced in CAG-CAT-USP18/α-MHC-Cre TG mice by tamoxifen treatment, which allowed Cre-mediated CAT gene excision.…”