Short-term hypoxia upregulated Mas receptor expression to repress the AT1 R signaling pathway and attenuate Ang II-induced cardiomyocyte apoptosis.

Abstract

Hypertension-stimulated cardiac hypertrophy and apoptosis play critical roles in the progression of heart failure. Our previous study suggested that hypertensive angiotensin II (Ang II) enhanced insulin-like growth factor receptor II (IGF-IIR) expression and cardiomyocyte apoptosis, which are involved JNK activation, sirtuin1 (SIRT1) degradation, and heat-shock transcription factor 1 (HSF1) acetylation. Moreover, previous studies have implied that short-term hypoxia (STH) might exert cardioprotective effects. However, the effects of STH on Ang II-induced cardiomyocyte apoptosis remain unknown. In this study, we found that STH reduced myocardial apoptosis caused by Ang II via upregulation of the Mas receptor (MasR) to inhibit the AT1 R signaling pathway. STH activates MasR to counteract the Ang II pro-apoptotic signaling cascade by inhibiting IGF-IIR expression via downregulation of JNK activation and reduction of SIRT1 degradation. Hence, HSF could remain deacetylated, and repress IGF-IIR expression. These effects decrease the activation of downstream pro-apoptotic and hypertrophic cascades and protect cardiomyocytes from Ang II-induced injury. In addition, we also found that silencing MasR expression enhanced Ang II-induced cardiac hypertrophy and the apoptosis signaling pathway. These findings suggest a critical role for MasR in cardiomyocyte survival. Altogether, our findings indicate that STH protects cardiomyocytes from Ang II-stimulated apoptosis. The protective effects of STH are associated with the upregulation of MasR to inhibit AT1 R signaling. STH could be a potential therapeutic strategy for cardiac diseases in hypertensive patients.