Synthetic retinoid Am80 reduces scavenger receptor expression and atherosclerosis in mice by inhibiting IL-6.
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-alpha/beta-specific agonist Am80, which is also an IL-6 inhibitor, can modulate macrophage lipid accumulation and foam cell formation.


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-1beta 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.
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Norifumi
N
Takeda
Ichiro
I
Manabe
Takayuki
T
Shindo
Hiroshi
H
Iwata
Satoshi
S
Iimuro
Hiroyuki
H
Kagechika
Koichi
K
Shudo
Ryozo
R
Nagai
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D001565:Benzoates / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology; D018955:CD36 Antigens / Q000032:analysis / Q000235:genetics; D002460:Cell Line; D015850:Interleukin-6 / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D051116:Receptors, Scavenger / Q000032:analysis / Q000187:drug effects*; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
D001057:Apolipoproteins E; D001565:Benzoates; D022782:CCAAT-Enhancer-Binding Protein-beta; D018955:CD36 Antigens; D015850:Interleukin-6; D051116:Receptors, Scavenger; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D000093242:Interleukin-6 Inhibitors; C061133:tamibarotene