title: HSF1 phosphorylation by ERK/GSK3 suppresses RNF126 to sustain IGF-IIR expression for hypertension-induced cardiomyocyte hypertrophy.
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 (AT1R). 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 HSF1S303phosphorylation, 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.
authors.affiliation: Translation Research Core, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Chih-Yang
authors.identifier: http://orcid.org/0000-0002-0266-3233
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung.
authors.forename: Fa-Lun
authors.initials: FL
authors.lastname: Lee
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Peng
authors.affiliation: Emergency Department, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Kuan-Ho
authors.initials: KH
authors.lastname: Lin
authors.affiliation: Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei.
authors.forename: Ray-Jade
authors.initials: RJ
authors.lastname: Chen
authors.affiliation: School of Chinese Medicine, China Medical University, Taichung, Taiwan.|Chinese Medicine Department, China Medical University Beigang Hospital, Taiwan.
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Ho
authors.affiliation: School of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Fu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.affiliation: Department of Biotechnology, Bharathiar University, Coimbatore, India.
authors.forename: Vijaya V
authors.initials: VV
authors.lastname: Padma
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung.|School of Chinese Medicine, China Medical University, Taichung, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000077405:Irbesartan; D018021:Lithium Chloride / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D055550:Protein Stability; D021381:Protein Transport; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C000619709:Hsf1 protein, rat; D044140:Receptor, Angiotensin, Type 1; D017527:Receptor, IGF Type 2; D013777:Tetrazoles; D000804:Angiotensin II; C000624656:Rnf126 protein, rat; D044767:Ubiquitin-Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D018021:Lithium Chloride; D000077405:Irbesartan
keywords: HSF1; IGF-IIR; RNF126; cardiac hypertrophy; hypertension