Heat shock factor 1-mediated transcription activation of Omi/HtrA2 induces myocardial mitochondrial apoptosis in the aging heart
Heat shock factor 1-mediated transcription activation of Omi/HtrA2 induces myocardial mitochondrial apoptosis in the aging heart
复制标题
热休克因子1介导的Omi/HtrA2转录激活诱导衰老心脏中的心肌线粒体凋亡
DOI：
10.18632/aging.102361
复制
发表时间：
2019-10-31
期刊：
影响因子：
5.2
通讯作者：
Ma, Xinliang
中科院分区：
文献类型：
--
作者：
Liu, Dan;Wu, Linguo;Ma, Xinliang
背景：心脏细胞凋亡增加是老年人的一个标志，这反过来又增加了心脏疾病的风险。Omi/HtrA 2 mRNA和蛋白的过度表达参与了老年心脏细胞凋亡。热休克因子1（Heat shock factor 1，HSF 1）是衰老心肌中与Omi/HtrA 2启动子结合的转录因子。然而，HSF 1是否通过Omi/HtrA 2的转录调控参与心肌细胞凋亡仍不清楚。本研究旨在探讨HSF 1是否在Omi/HtrA 2转录调节和心肌细胞凋亡中发挥作用。方法和结果：对不同年龄小鼠心脏进行评估，结果表明心脏功能储备下降，线粒体凋亡增加。老年人Omi/HtrA 2过表达与运动负荷后左室功能呈负相关，与心肌Caspase-9凋亡呈正相关。衰老心脏的染色质免疫沉淀（ChIP）和H9 C2细胞的质粒转染/RNA干扰揭示了HSF 1表达的增强通过诱导Omi/HtrA 2的启动子活性来促进Omi/HtrA 2的表达，同时也通过上调Omi/HtrA 2的表达来增加线粒体凋亡。HSF 1作为一种转录因子，诱导衰老心肌细胞Omi/HtrA 2表达和Caspase-9凋亡，同时也降低心脏储备功能。
Background: Increased cardiac apoptosis is a hallmark of the elderly, which in turn increases the risk for developing cardiac disease. The overexpression of Omi/HtrA2 mRNA and protein contributes to apoptosis in the aged heart. Heat shock factor 1 (HSF1) is a transcription factor that binds to the promoter of Omi/HtrA2 in the aging myocardium. However, whether HSF1 participates in cardiomyocyte apoptosis via transcriptional regulation of Omi/HtrA2 remains unclear. The present study was designed to investigate whether HSF1 plays a role in Omi/HtrA2 transcriptional regulation and myocardial apoptosis.Methods and Results: Assessment of the hearts of mice of different ages was performed, which indicated a decrease in cardiac function reserve and an increase in mitochondrial apoptosis. Omi/HtrA2 overexpression in the elderly was negatively correlated with left ventricular function after exercise overload and positively correlated with myocardial Caspase-9 apoptosis. Chromatin immunoprecipitation (ChIP) of aging hearts and plasmid transfection/RNA interference of H9C2 cells revealed that enhancement of HSF1 expression promotes Omi/HtrA2 expression by inducing the promoter activity of Omi/HtrA2 while also increasing mitochondrial apoptosis by upregulating Omi/HtrA2 expression.Conclusions: HSF1 acts as a transcriptional factor that induces Omi/HtrA2 expression and Caspase-9 apoptosis in aged cardiomyocytes, while also decreasing cardiac function reserve.