School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.
Division of Cardiology, Department of Internal Medicine, Taichung Armed Force Taichung General Hospital, Taichung, Taiwan.
J Cell Biochem. 2018 Mar;119(3):2742-2749. doi: 10.1002/jcb.26440. Epub 2017 Nov 24.
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 AT 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 AT R signaling. STH could be a potential therapeutic strategy for cardiac diseases in hypertensive patients.
高血压刺激的心肌肥大和凋亡在心力衰竭的进展中起着关键作用。我们之前的研究表明，高血压血管紧张素 II（Ang II）增强胰岛素样生长因子受体 II（IGF-IIR）的表达和心肌细胞凋亡，涉及 JNK 激活、sirtuin1（SIRT1）降解和热休克转录因子 1（HSF1）乙酰化。此外，先前的研究表明，短期缺氧（STH）可能发挥心脏保护作用。然而，STH 对 Ang II 诱导的心肌细胞凋亡的影响尚不清楚。在这项研究中，我们发现 STH 通过上调 Mas 受体（MasR）减少 Ang II 引起的心肌细胞凋亡，从而抑制 AT R 信号通路。STH 通过抑制 IGF-IIR 表达、降低 JNK 激活和减少 SIRT1 降解来激活 MasR，从而拮抗 Ang II 的促凋亡信号级联。因此，HSF 可以保持去乙酰化，并抑制 IGF-IIR 的表达。这些作用减少了下游促凋亡和肥大级联的激活，并保护心肌细胞免受 Ang II 诱导的损伤。此外，我们还发现沉默 MasR 表达增强了 Ang II 诱导的心肌肥大和凋亡信号通路。这些发现表明 MasR 在心肌细胞存活中起着关键作用。总之，我们的研究结果表明，STH 可保护心肌细胞免受 Ang II 刺激的凋亡。STH 的保护作用与上调 MasR 抑制 AT R 信号有关。STH 可能是高血压患者心脏疾病的一种潜在治疗策略。
