Published Online
on May 6, 2002

A more recent version of this article appeared on May 21, 2002

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Submitted on September 30, 2001
Revised on February 27, 2002
Accepted on February 28, 2002

Functional Inhibition of Ras by S-trans, trans-Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice

Jacob George MD, Arnon Afek MD, Pnina Keren PhD, Itzhak Herz MD, Iris Goldberg PhD, Roni Haklai PhD, Yoel Kloog PhD, and Gad Keren MD^*

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

^* To whom correspondence should be addressed. E-mail: kereng{at}tasmc.health.gov.il.

Background—Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis.

Methods and Results—We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E--deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-B expression were considerably reduced compared with controls.

Conclusions—FTS suppressed atherosclerotic plaques in apolipoprotein E--deficient mice, providing a useful tool for research in atherosclerosis.

Key words: atherosclerosis • Ras • immune system • apolipoproteins

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