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HSF1 phosphorylation by ERK/GSK3 suppresses RNF126 to sustain IGF-IIR expression for hypertension-induced cardiomyocyte hypertrophy.

Authors
  • Huang, Chih-Yang1
  • Lee, Fa-Lun2
  • Peng, Shu-Fen3
  • Lin, Kuan-Ho4
  • Chen, Ray-Jade5
  • Ho, Tsung-Jung6, 7
  • Tsai, Fu-Jen6
  • Padma, Vijaya V8
  • Kuo, Wei-Wen3
  • Huang, Chih-Yang2, 6, 9
  • 1 Translation Research Core, China Medical University Hospital, China Medical University, Taichung, Taiwan. , (China)
  • 2 Graduate Institute of Basic Medical Science, China Medical University, Taichung. , (China)
  • 3 Department of Biological Science and Technology, China Medical University, Taichung, Taiwan. , (China)
  • 4 Emergency Department, China Medical University Hospital, Taichung, Taiwan. , (China)
  • 5 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei.
  • 6 School of Chinese Medicine, China Medical University, Taichung, Taiwan. , (China)
  • 7 Chinese Medicine Department, China Medical University Beigang Hospital, Taiwan. , (China)
  • 8 Department of Biotechnology, Bharathiar University, Coimbatore, India. , (India)
  • 9 Department of Health and Nutrition Biotechnology, Asia University, Taichung.
Type
Published Article
Journal
Journal of Cellular Physiology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Feb 01, 2018
Volume
233
Issue
2
Pages
979–989
Identifiers
DOI: 10.1002/jcp.25945
PMID: 28383811
Source
Medline
Keywords
License
Unknown

Abstract

Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure (HF). Inhibition of extracellular signal-regulated kinases (ERK) efficaciously suppressed angiotensin II (ANG II)-induced cardiomyocyte hypertrophy and apoptosis by blocking insulin-like growth factor II receptor (IGF-IIR) signaling. However, the detailed mechanism by which ANG II induces ERK-mediated IGF-IIR signaling remains elusive. Here, we found that ANG II activated ERK to upregulate IGF-IIR expression via the angiotensin II type I receptor (AT1 R). ERK activation subsequently phosphorylates HSF1 at serine 307, leading to a secondary phosphorylation by glycogen synthase kinase III (GSK3) at serine 303. Moreover, we found that ANG II mediated ERK/GSK3-induced IGF-IIR protein stability by downregulating the E3 ubiquitin ligase of IGF-IIR RING finger protein CXXVI (RNF126). The expression of RNF126 decreased following ANG II-induced HSF1S303 phosphorylation, resulting in IGF-IIR protein stability and increased cardiomyocyte injury. Inhibition of GSK3 significantly alleviated ANG II-induced cardiac hypertrophy in vivo and in vitro. Taken together, these results suggest that HSF1 phosphorylation stabilizes IGF-IIR protein stability by downregulating RNF126 during cardiac hypertrophy. ANG II activates ERK/GSK3 to phosphorylate HSF1, resulting in RNF126 degradation, which stabilizes IGF-IIR protein expression and eventually results in cardiac hypertrophy. HSF1 could be a valuable therapeutic target for cardiac diseases among hypertensive patients.

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