Adenovirus-mediated transfer of a dominant-negative H-ras suppresses neointimal formation in balloon-injured arteries in vivo

Hikaru Ueno, Hiroaki Yamamoto, Shin Ichi Ito, Jian Jun Li, Akira Takeshita

Research output: Contribution to journalArticle

80 Citations (Scopus)

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 β-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.

Original languageEnglish
Pages (from-to)898-904
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume17
Issue number5
DOIs
Publication statusPublished - Jan 1 1997

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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