Dysregulation of HSG triggers vascular proliferative disorders
Kuang-Hueih Chen1, Xiaomei Guo, Dalong Ma
1The Institute of Cardiovascular Science & The Institute of Molecular Medicine, Peking University, Beijing 100083, China.
Insights
A novel gene, hyperplasia suppressor gene (HSG), also known as rat mitofusin-2, was identified as a key regulator of vascular cell proliferation. Reduced HSG expression is linked to cardiovascular diseases like atherosclerosis and restenosis.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Genetics
Background:
- Vascular proliferative disorders, including atherosclerosis and restenosis, are leading causes of cardiovascular disease.
- A common underlying molecular mechanism for these conditions has not been fully elucidated.
Purpose of the Study:
- To identify and characterize a novel gene involved in suppressing vascular hyperplasia.
- To investigate the role of this gene in the pathogenesis of vascular proliferative disorders.
Main Methods:
- Identified and characterized a novel hyperplasia suppressor gene (HSG), later identified as rat mitofusin-2 (rHSG).
- Assessed HSG expression levels in vascular smooth muscle cells (VSMCs) from various disease models (spontaneously hypertensive rats, balloon-injured rats, ApoE-knockout mice).
- Evaluated the effect of HSG overexpression on VSMC proliferation in vitro and neointimal hyperplasia in vivo.
Main Results:
- HSG expression was significantly reduced in hyper-proliferative VSMCs from diseased arteries.
- Overexpression of HSG suppressed VSMC proliferation, inhibited ERK/MAPK signaling, and induced cell-cycle arrest.
- HSG effectively blocked balloon injury-induced neointimal VSMC proliferation and restenosis in rat carotid arteries.
- The anti-proliferative effect was independent of mitochondrial fusion, linked to the p21(ras) motif.
Conclusions:
- Rat mitofusin-2 (rHSG) functions as a crucial suppressor of vascular cell proliferation.
- Dysregulation or reduced expression of rHSG contributes to the development of vascular proliferative disorders such as atherosclerosis and restenosis.
- rHSG represents a potential therapeutic target for cardiovascular diseases.
Abstract:
Vascular proliferative disorders, such as atherosclerosis and restenosis, are the most common causes of severe cardiovascular diseases, but a common molecular mechanism remains elusive. Here, we identify and characterize a novel hyperplasia suppressor gene, named HSG (later re-named rat mitofusin-2). HSG expression was markedly reduced in hyper-proliferative vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rat arteries, balloon-injured Wistar Kyoto rat arteries, or ApoE-knockout mouse atherosclerotic arteries. Overexpression of HSG overtly suppressed serum-evoked VSMC proliferation in culture, and blocked balloon injury induced neointimal VSMC proliferation and restenosis in rat carotid arteries. The HSG anti-proliferative effect was mediated by inhibition of ERK/MAPK signalling and subsequent cell-cycle arrest. Deletion of the p21(ras) signature motif, but not the mitochondrial targeting domain, abolished HSG-induced growth arrest, indicating that rHSG-induced anti-proliferation was independent of mitochondrial fusion. Thus, rHSG functions as a cell proliferation suppressor, whereas dysregulation of rHSG results in proliferative disorders.
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