on February 16, 2006
Published online before print February 16, 2006, doi: 10.1161/01.ATV.0000214296.94849.1c
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Submitted on August 31, 2005
Accepted on February 3, 2006
Synthetic Retinoid Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-6
Norifumi Takeda ;
From the Department of Cardiovascular Medicine (N.T., H.I., S.I., R.N.) and Nano Bioengineering Education Program (I.M.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Matsumoto, Japan (T.S.), School of Biomedical Science, Tokyo Medical and Dental University, Tokyo (H.K.); Research Foundation Itsuu Laboratory (K.S.), Tokyo, Japan.
* To whom correspondence should be addressed. E-mail: nagai-tky{at}umin.ac.jp.
Background--Macrophage scavenger receptors facilitate the uptake of modified low-density lipoprotein (LDL), formation of foam cells, and development of atherosclerosis. Given that proinflammatory cytokines, including IL-6, can modulate the macrophage foaming process, the aim of the present study was to determine whether the synthetic retinoic acid receptor-
/
-specific agonist Am80, which is also an IL-6 inhibitor, can modulate macrophage lipid accumulation and foam cell formation.
Methods and Results--Am80 suppressed IL-6 production induced by 12-myristate 13-acetate (PMA) or angiotensin II in mouse Raw264 macrophages. It also suppressed expression of the 2 major scavenger receptors (scavenger receptor-A [SR-A] and CD36), in part by inhibiting IL-6, and inhibited macrophage foam cell formation. Systemic administration of Am80 led to reductions in the areas of atherosclerotic lesions and foam cell accumulation in the aortas of apolipoprotein E (apoE)-deficient mice and reduced serum concentrations of IL-6 and IL-1 without affecting body weights, serum lipid profiles or IL-10 levels.
Conclusions--Am80 suppresses scavenger receptor expression and macrophage foam cell formation in vitro and prevents atherogenesis in apoE-deficient mice in vivo. This suggests Am80 is a novel candidate agent that could be highly useful in the prevention and treatment of atherosclerosis.
Key words: macrophage • IL-6 • CD36 • scavenger receptor-A • retinoid
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