This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 24/2/363    most recent 01.ATV.0000112021.98971.f0v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by George, J. Articles by Keren, G. Search for Related Content PubMed PubMed Citation Articles by George, J. Articles by Keren, G. Related Collections Restenosis Cell signalling/signal transduction Smooth muscle proliferation and differentiation Angioplasty and Stenting

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:363.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Inhibition of Intimal Thickening in the Rat Carotid Artery Injury Model by a Nontoxic Ras Inhibitor

Jacob George; Jessica Sack; Iris Barshack; Pnina Keren; Iris Goldberg; Roni Haklai; Galit Elad-Sfadia; Yoel Kloog; Gad Keren

From the Department of Cardiology and the Cardiovascular Research Laboratory (J.G., J.S., P.K., G.K.), Tel Aviv Sourasky Medical Center, Tel Aviv University, Sackler School of Medicine, Israel; Institute of Pathology (I.B., I.G.), Sheba Medical Center, Israel; and the Department of Neurobiochemistry (R.H., G.E.-S., Y.K.), Tel Aviv University, Israel.

Correspondence to Dr Jacob George, Department of Cardiology, Sourasky, Tel-Aviv Medical Center, 6 Weizmann St, Tel-Aviv, Israel. E-mail jacobg{at}post.tau.ac.il

Background— Neointimal formation with and without previous vascular injury is common after balloon dilation and in transplant arteriosclerosis. It involves proliferation and migration of medial smooth muscle cells and inflammation, processes that are regulated by Ras proteins and their down-stream effectors. Farnesylthiosalicylate (FTS) is a Ras inhibitor that interferes with Ras membrane anchorage and affects Ras proteins in their active state. In the present study, we tested the hypothesis that systemic administration of FTS will suppress intimal thickening in the rat carotid injury model.

Methods and Results— The effects of FTS on rat vascular smooth muscle cells (VSMC) and splenocytes proliferation were evaluated in vitro. The in vivo effects of FTS on the neointima of balloon-injured male Wistar rats, treated daily for 2 weeks with FTS (5 mg/kg weight, intraperitoneally) were evaluated by determination of Ras, Ras-GTP, and active ERK levels (3 days after injury), and by quantitative determination of the extent of intimal thickening and immunohistochemistry for Ras, iNOS, NFkB, and Ki-67 (2 weeks after injury). FTS inhibited VSMC and splenocyte proliferation as well as interferon- secretion by splenocytes in a dose-dependent manner. Compared with controls, FTS treatment resulted in a strong decrease in Ras-GTP and active ERK, and it significantly reduced intimal thickening after the injury. Ras expression appeared predominantly at areas of neointima regardless of the treatment group. NFkB and iNOS-positive cell numbers were reduced in sections of FTS treated rats.

Conclusion— FTS appears to act as a potent inhibitor of intimal thickening in a model of experimental arterial injury.

Key Words: intimal thickening • Ras • smooth muscle cell • proliferation

This article has been cited by other articles:

				J. Xu, F. A. Ismat, T. Wang, J. Yang, and J. A. Epstein NF1 Regulates a Ras-Dependent Vascular Smooth Muscle Proliferative Injury Response Circulation, November 6, 2007; 116(19): 2148 - 2156. [Abstract] [Full Text] [PDF]