Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:898-904
© 1997 American Heart Association, Inc.
Articles |
Adenovirus-Mediated Transfer of a Dominant-Negative H-ras Suppresses Neointimal Formation in Balloon-Injured Arteries In Vivo
From the Molecular Cardiology Unit, Department of Cardiology, Kyushu University School of Medicine (H.U., H.Y., J.-J.L., A.T.), and the Department of Dental Anesthesiology, Kyushu University School of Dentistry (S-i.I.), Fukuoka, Japan.
Correspondence to Hikaru Ueno, MD, PhD, Department of Cardiology, Kyushu University School of Medicine, Fukuoka, 812-82 Japan. E-mail ueno{at}cardiol.med.kyushu-u.ac.jp
Abstract Abnormal migration and proliferation of arterial smooth muscle cells may be a central event in inflammatory proliferative arterial diseases such as atherosclerosis and restenosis after angioplasty. The proto-oncogene c-H-ras is considered to be a key transducer in various growth-signaling events. We constructed an adenoviral vector (AdexCAHRasY57) expressing a potent dominant-negative mutated form of c-H-ras in which tyrosine replaces aspartic acid at residue 57. Infection of smooth muscle cells with AdexCAHRasY57 produced a large quantity of H-ras-p21, completely inhibited serum-stimulated activation of mitogen-activated protein kinase, and abolished the DNA synthesis in response to serum mitogens. However, a surge of intracellular Ca2+ concentration in response to platelet-derived growth factor was not affected, suggesting that some cellular functions were preserved. When we applied AdexCAHRasY57 into balloon-injured rat carotid arteries from inside the lumen, neointimal formation was significantly reduced (neointima/media ratio: 0.28) compared with that (1.50) in arteries treated with either injury alone or injury and infection with a control adenovirus, AdexCALacZ, expressing bacterial ß-galactosidase. Our results suggest that adenovirus-mediated arterial transfer of dominant-negative H-ras may be a practical form of effective molecular intervention for proliferative arterial diseases.
Key Words: adenoviral transfer • neointima • balloon injury
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