Heat shock transcription factor 1 protects heart after pressure overload through promoting myocardial angiogenesis in male mice.

Abstract

Heat shock transcription factor 1 (HSF1) plays an important role not only in excise-induced cardiac hypertrophy but also in protection against pressure overload-induced cardiac dysfunction. However, the mechanism is not completely understood. We here elucidate the potential mechanisms by which HSF1 protects against pressure overload-induced cardiac remodeling and dysfunction. A sustained constriction of transverse aorta (TAC) was imposed to HSF1 transgenic (TG), knockout (KO) and their littermate wild type (WT) male mice. Four weeks later, adaptive responses to TAC, such as cardiac hypertrophy, contractility and angiogenesis evaluated by echocardiography, catheterization, coronary perfusion pressure and immunohistochemistry were well preserved in TG but not in KO compared with WT mice. An angiogenesis inhibitor TNP-470 abrogated all these adaptive responses in TG mice, while cardiac transfection of VEGF with angiopoietin-1 rescued the broken heart in KO mice. In response to TAC, p53 was downregulated and hypoxia-inducing transcription factor-1 (HIF-1) was upregulated not only in the heart but also in the cultured cardiac endothelial cells (EC) of TG mice as compared to WT mice whereas these changes became opposite in KO mice. A small interfering RNA (siRNA) of HIF-1 but not a p53 gene impaired the adaptive responses of the heart and EC in TG mice, and a siRNA of p53 but not a HIF-1 gene significantly reversed the heart and EC disorders in KO mice after TAC. We conclude that HSF1 promotes cardiac angiogenesis through suppression of p53 and subsequent upregulation of HIF-1 in endothelial cells during chronic pressure overload, leading to the maintenance of cardiac adaptation.

• Authors: Yunzeng Zou, Jiming Li, Hong Ma, Hong Jiang, Jie Yuan, Hui Gong, Yanyan Liang, Aili Guan, Jian Wu, Lei Li, Ning Zhou, Yuhong Niu, Aijun Sun, Akira Nakai, Ping Wang, Hiroyuki Takano, Issei Komuro, Junbo Ge
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 51 Issue 5 Pg. 821-9 (Nov 2011) ISSN: 1095-8584 [Electronic] England
• PMID: 21854784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Angiopoietin-1
• Cyclohexanes
• DNA-Binding Proteins
• Heat Shock Transcription Factors
• Hsf1 protein, mouse
• RNA, Small Interfering
• Sesquiterpenes
• Transcription Factors
• Tumor Suppressor Protein p53
• O-(Chloroacetylcarbamoyl)fumagillol

Topics

• Angiogenesis Inhibitors (adverse effects)
• Angiopoietin-1 (genetics, metabolism)
• Animals
• Cardiomegaly (diagnostic imaging, etiology, genetics, metabolism, pathology, physiopathology)
• Cells, Cultured
• Constriction
• Cyclohexanes (adverse effects)
• DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• Echocardiography
• Endothelial Cells (cytology, drug effects, metabolism)
• Gene Silencing (drug effects)
• Heat Shock Transcription Factors
• Male
• Mice
• Mice, Knockout
• Mice, Transgenic
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• Neovascularization, Physiologic (drug effects, genetics)
• O-(Chloroacetylcarbamoyl)fumagillol
• Pressure (adverse effects)
• RNA, Small Interfering (pharmacology)
• Sesquiterpenes (adverse effects)
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Transfection
• Tumor Suppressor Protein p53 (antagonists & inhibitors, genetics, metabolism)
• Ventricular Dysfunction, Left (diagnostic imaging, etiology, genetics, metabolism, pathology, physiopathology)