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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1177.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Synthetic Retinoid Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-6

Norifumi Takeda; Ichiro Manabe; Takayuki Shindo; Hiroshi Iwata; Satoshi Iimuro; Hiroyuki Kagechika; Koichi Shudo; Ryozo Nagai

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.

Correspondence to Ryozo Nagai, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. 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-/ß-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-1ß 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.

Synthetic retinoid Am80 inhibits IL-6 signaling and suppresses scavenger receptor expession in macrophages. Moreover, Am80 prevents macrophage from cell formation in vitro and inhibited atherogenesis in apoE-dificient moce. 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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