Promotion of CHIP-Mediated p53 Degradation Protects the Heart From Ischemic Injury

Abstract

Rationale: The number of patients with coronary heart disease, including myocardial infarction, is increasing and novel therapeutic strategy is awaited. Tumor suppressor protein p53 accumulates in the myocardium after myocardial infarction, causes apoptosis of cardiomyocytes, and plays an important role in the progression into heart failure. Objectives: We investigated the molecular mechanisms of p53 accumulation in the heart after myocardial infarction and tested whether anti-p53 approach would be effective against myocardial infarction. Methods and Results: Through expression screening, we found that CHIP (carboxyl terminus of Hsp70-interacting protein) is an endogenous p53 antagonist in the heart. CHIP suppressed p53 level by ubiquitinating and inducing proteasomal degradation. CHIP transcription was downregulated after hypoxic stress and restoration of CHIP protein level prevented p53 accumulation after hypoxic stress. CHIP overexpression in vivo prevented p53 accumulation and cardiomyocyte apoptosis after myocardial infarction. Promotion of CHIP function by heat shock protein (Hsp)90 inhibitor, 17-allylamino-17-demethoxy geldanamycin (17-AAG), also prevented p53 accumulation and cardiomyocyte apoptosis both in vitro and in vivo. CHIP-mediated p53 degradation was at least one of the cardioprotective effects of 17-AAG. Conclusions: We found that downregulation of CHIP level by hypoxia was responsible for p53 accumulation in the heart after myocardial infarction. Decreasing the amount of p53 prevented myocardial apoptosis and ameliorated ventricular remodeling after myocardial infarction. We conclude that anti-p53 approach would be effective to treat myocardial infarction. (Circ Res. 2010;106:1692-1702.)

Circulating p53-Responsive MicroRNAs Are Predictive Indicators of Heart Failure After Acute Myocardial Infarction

“…Furthermore, transfer of these extracellular microRNAs accelerated cell death ( Figure 3). Taken together with our recent finding that p53 accumulation in the myocardium in response to pressure overload or after MI plays an essential role in HF progression in mice, 12,13 our present results suggest that activation of p53 and the increased expression of the p53-responsive microRNAs, miR-192, miR-194, and miR-34a, are likely involved in the pathogenesis of HF after AMI. However, it remains undetermined whether circulating p53-responsive microRNAs were derived from infarct or ischemic heart tissues.…”

Apoptosis in Heart Failure - The Role of the .BETA.-Adrenergic Receptor-Mediated Signaling Pathway and p53-Mediated Signaling Pathway in the Apoptosis of Cardiomyocytes -

“…43 In addition, overexpressing CHIP, which induces the degradation of p53, attenuated the accumulation of p53 and reduced cardiomyocyte apoptosis after myocardial infarction. 4 These findings indicate that p53 promotes the deterioration of cardiac function.…”

Effect of Diazoxide Preconditioning on Cultured Rat Myocardium Microvascular Endothelial Cells against Apoptosis and Relation of PI3K/Akt Pathway

“…It is recognized as one of the pro-apoptotic genes, and p53 transcriptional activity increased when ischemia and hypoxia (16), mediating apoptosis of p53-dependent myocardial cells (17). In this study, we found that expression level of p53 mRNA enhanced significantly after H/R, which showed p53 have participated in the apoptosis of MMECs caused by H/R.…”