ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation.
Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Our previous studies found that the activation of insulin-like growth factor receptor II (IGF-IIR) signaling was critical for hypertensive angiotensin II (ANG II)-induced cardiomyocyte apoptosis. However, the detailed mechanism by which ANG II regulates IGF-IIR in heart cells remains elusive. In this study, we found that ANG II activated its downstream kinase JNK to increase IGF-IIR expression through the ANG II receptor angiotensin type 1 receptor. JNK activation subsequently led to sirtuin 1 (SIRT1) degradation via the proteasome, thus preventing SIRT1 from deacetylating heat-shock transcription factor 1 (HSF1). The resulting increase in the acetylation of HSF1 impaired its ability to bind to the IGF-IIR promoter region (nt -748 to -585). HSF1 protected cardiomyocytes by acting as a repressor of IGF-IIR gene expression, and ANG II diminished this HSF1-mediated repression through enhanced acetylation, thus activating the IGF-IIR apoptosis pathway. Taken together, these results suggest that HSF1 represses IGF-IIR gene expression to protect cardiomyocytes. ANG II activates JNK to degrade SIRT1, resulting in HSF1 acetylation, which induces IGF-IIR expression and eventually results in cardiac hypertrophy and apoptosis. HSF1 could be a valuable target for developing treatments for cardiac diseases in hypertensive patients.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC.
C-Y
CY
Huang
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, ROC.
W-W
WW
Kuo
1] Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan, ROC [2] Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan, ROC.
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YL
Yeh
1] Chinese Medicine Department, China Medical University Beigang Hospital, Beigang, Taiwan, ROC [2] School of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC.
T-J
TJ
Ho
1] Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan, ROC [2] Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan, ROC.
J-Y
JY
Lin
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC.
D-Y
DY
Lin
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC.
C-H
CH
Chu
School of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC.
F-J
FJ
Tsai
Department of Healthcare Administration, Asia University, Taichung, Taiwan, ROC.
C-H
CH
Tsai
1] Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC [2] School of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC [3] Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, ROC.
C-Y
CY
Huang
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D005260:Female; D000076249:Heat Shock Transcription Factors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D017527:Receptor, IGF Type 2; D014157:Transcription Factors; D000804:Angiotensin II; D048031:JNK Mitogen-Activated Protein Kinases; D056564:Sirtuin 1