Novel signaling axis of FHOD1-RNF213-Col1α/Col3α in the pathogenesis of hypertension-induced tunica media thickening
Copyright © 2023. Published by Elsevier Ltd..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:182 |
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| Enthalten in: |
Journal of molecular and cellular cardiology - 182(2023) vom: 05. Sept., Seite 57-72 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Yuanyuan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.08.2023 Date Revised 24.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.yjmcc.2023.07.008 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359822851 |
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| 100 | 1 | |a Chen, Yuanyuan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Novel signaling axis of FHOD1-RNF213-Col1α/Col3α in the pathogenesis of hypertension-induced tunica media thickening |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 24.08.2023 | ||
| 500 | |a Date Revised 24.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023. Published by Elsevier Ltd. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Collagen-1 and collagen-3 | |
| 650 | 4 | |a FHOD1 | |
| 650 | 4 | |a Hypertension | |
| 650 | 4 | |a Hypertrophy | |
| 650 | 4 | |a Phosphorylation | |
| 650 | 4 | |a RNF213 | |
| 650 | 4 | |a Tunica media | |
| 650 | 4 | |a Vascular smooth muscle cells | |
| 650 | 7 | |a Actins |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Rnf213 protein, rat |2 NLM | |
| 700 | 1 | |a Yuan, Yuchan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yuhan |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Xueze |e verfasserin |4 aut | |
| 700 | 1 | |a Hua, Xuesheng |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhiyong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Julie |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Zhenwei |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yongqin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qunshan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yigang |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yuepeng |e verfasserin |4 aut | |
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