2. Academic Validation
  3. Novel signaling axis of FHOD1-RNF213-Col1α/Col3α in the pathogenesis of hypertension-induced tunica media thickening

Novel signaling axis of FHOD1-RNF213-Col1α/Col3α in the pathogenesis of hypertension-induced tunica media thickening

  • J Mol Cell Cardiol. 2023 Jul 21;182:57-72. doi: 10.1016/j.yjmcc.2023.07.008.
Yuanyuan Chen 1,  Yuchan Yuan 1,  Yuhan Chen 1,  Xueze Jiang 1,  Xuesheng Hua 1,  Zhiyong Chen 1,  Julie Wang 2,  Hua Liu 3,  Qing Zhou 1,  Ying Yu 1,  Zhenwei Yang 1,  Yi Yu 1,  Yongqin Wang 4,  Qunshan Wang 1,  Yigang Li 1,  Jie Chen 5,  Yuepeng Wang 6
Affiliations

Affiliations

  • 1 Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
  • 2 Department of Computer Science, Brown University, Providence, RI 02912, USA.
  • 3 Department of Intensive Care Med, Zhongshan Hospital of Fudan University, Shanghai 200032, China.
  • 4 Division of Rheumatology and Immunology, University of Toledo Medical center, 3120 Glendale Avenue, Toledo, OH 43614, USA.
  • 5 Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. Electronic address: jieyuepeng@msn.com.
  • 6 Molecular Cardiology Research Laboratory, Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. Electronic address: wangyuepeng@xinhuamed.com.cn.
PMID: 37482037 DOI: 10.1016/j.yjmcc.2023.07.008
Abstract

Hypertension-induced tunica media thickening (TMT) is the most important fundamental for the subsequent complications like stroke and cardiovascular diseases. Pathogenically, TMT originates from both vascular smooth muscle cells (VSMCs) hypertrophy due to synthesizing more amount of intracellular contractile proteins and excess secretion of extracellular matrix. However, what key molecules are involved in the pathogenesis of TMT is unknown. We hypothesize that formin homology 2 domain-containing protein 1 (FHOD1), an amply expressed mediator for assembly of thin actin filament in VSMCs, is a key regulator for the pathogenesis of TMT. In this study, we found that FHOD1 expression and its phosphorylation/activation were both upregulated in the arteries of three kinds of hypertensive rats. Ang-II induced actin filament formation and hypertrophy through activation and upregulation of FHOD1 in VSMCs. Active FHOD1-mediated actin filament assembly and secretions of collagen-1α/collagen-3α played crucial roles in Ang-II-induced VSMCs hypertrophy in vitro and hypertensive TMT in vivo. Proteomics demonstrated that activated FL-FHOD1 or its C-terminal diaphanous-autoregulatory domain significantly upregulated RNF213 (ring finger protein 213), a 591-kDa cytosolic E3 ubiquitin Ligase with its loss-of-functional mutations being a susceptibility gene for Moyamoya disease which has prominent tunica media thinning in both intracranial and systemic arteries. Mechanistically, activated FHOD1 upregulated its downstream effector RNF213 independently of its classical pathway of decreasing G-actin/F-actin ratio, transcription, and translation, but dependently on its C-terminus-mediated stabilization of RNF213 protein. FHOD1-RNF213 signaling dramatically promoted collagen-1α/collagen-3α syntheses in VSMCs. Our results discovered a novel signaling axis of FHOD1-RNF213-collagen-1α/collagen-3α and its key role in the pathogenesis of hypertensive TMT.

Keywords

Collagen-1 and collagen-3; FHOD1; Hypertension; Hypertrophy; Phosphorylation; RNF213; Tunica media; Vascular smooth muscle cells.

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