Research Paper|Volume 11, Issue 20|pp 8982—8997

Heat shock factor 1-mediated transcription activation of Omi/HtrA2 induces myocardial mitochondrial apoptosis in the aging heart

Dan Liu¹, Linguo Wu², Ye Wu^3,⁴, Xin Wei³, Wen Wang³, Suli Zhang^3,⁴, Ming Yi³, Jing Li⁵, Huirong Liu^3,⁴, Xinliang Ma⁶

¹Department of Physiology and Pathophysiology, Yan Jing Medical College, Capital Medical University, Beijing 101300, China
²Department of Pathology, Beijing LuHe Hospital of Capital Medical University, Beijing 101100, China
³Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
⁴Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease, Beijing 100069, China
⁵Department of Cardiology, XuanWu Hospital Capital Medical University, Beijing 100053, China
⁶Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA

Received: April 10, 2019Accepted: October 5, 2019Published: October 18, 2019

Copyright © 2019 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.