Dysregulation of HSG triggers vascular proliferative disorders.
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.
Chen
Kuang-Hueih
KH
The Institute of Cardiovascular Science & The Institute of Molecular Medicine, Peking University, Beijing 100083, China.
Guo
Xiaomei
X
Ma
Dalong
D
Guo
Yanhong
Y
Li
Qian
Q
Yang
Dongmei
D
Li
Pengfei
P
Qiu
Xiaoyan
X
Wen
Shaojun
S
Xiao
Rui-Ping
RP
Tang
Jian
J
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000473:pathology; D002455:Cell Division; D023903:Coronary Restenosis / Q000209:etiology; D020558:GTP Phosphohydrolases; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000378:metabolism / Q000502:physiology; D051381:Rats
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; D015689:Oncogene Protein p21(ras)