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Dysregulation of HSG triggers vascular proliferative disorders

Nature Cell Biology volume 6, pages 872–883 (2004)Cite this article

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 p21ras 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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Figure 1: rHSG is downregulated in highly proliferative vascular smooth muscle cells (VSMCs).
Figure 2: Overexpression of rHSG inhibits serum-stimulated VSMC proliferation.
Figure 3: rHSG-induced cell cycle arrest is associated with increased p21 and p27 abundance and reduced phosphorylation of Rb.
Figure 4: Binding of rHSG to Ras inhibits the Ras–Raf–ERK1/2 signalling pathway in WKY VSMCs.
Figure 5: Mitochondrial targeting is not required for rHSG-mediated inhibition of ERK1/2 signalling and anti-proliferation.
Figure 6: Adenoviral gene transfer of rHSG inhibits VSMC proliferation in balloon-injured rat carotid arteries.
Figure 7: Downregulation of rHSG in atherosclerotic carotid arteries from ApoE-knockout mice.
Figure 8: Overexpression of rHSG prevents balloon-injury induced restenosis in rat carotid arteries.

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Acknowledgements

This work was supported by the National Basic Research Priorities Program 973 (G1998051015 and G2000056906), China's 863 High-Tech National Research Programme, Chinese Young Investigator Award (30225036), Peking University 985 Project. The authors would like to thank D. Longo, H. Cheng, E.G. Lakatta, P. Morin, X. Fu and J. Chen for critical reading and discussions. We would also like to thank M. Wang and J. Zhang for excellent technical support.

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Authors and Affiliations

  1. The Institute of Cardiovascular Science & The Institute of Molecular Medicine, Peking University, Beijing, 100083, China

    Kuang-Hueih Chen, Yanhong Guo, Qian Li, Pengfei Li, Shaojun Wen, Rui-Ping Xiao & Jian Tang

  2. Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, 21224, MD, USA

    Kuang-Hueih Chen, Xiaomei Guo, Dongmei Yang & Rui-Ping Xiao

  3. Center for Human Disease Genomics and Department of Immunology, Health Center of Peking University, Beijing, 100083, China

    Dalong Ma & Xiaoyan Qiu

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Chen, KH., Guo, X., Ma, D. et al. Dysregulation of HSG triggers vascular proliferative disorders. Nat Cell Biol 6, 872–883 (2004). https://doi.org/10.1038/ncb1161

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