Retinoic acid induces macrophage cholesterol efflux and inhibits atherosclerotic plaque formation in apoE-deficient mice.

Abstract

It has been suggested that retinoic acid (RA) has a potential role in the prevention of atherosclerotic CVD. In the present study, we used J774A.1 cell lines and primary peritoneal macrophages to investigate the protective effects of RA on foam cell formation and atherogenesis in apoE-deficient (apoE- / -) mice. A total of twenty male apoE- / - mice (n 10 animals per group), aged 8 weeks, were fed on a high-fat diet (HFD) and treated with vehicle or 9-cis-RA for 8 weeks. The atherosclerotic plaque area in the aortic sinus of mice in the 9-cis-RA group was 40·7 % less than that of mice in the control group (P< 0·01). Mouse peritoneal macrophages from the 9-cis-RA group had higher protein expression levels of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) than those from the control group. Serum total and LDL-cholesterol concentrations were lower in the 9-cis-RA group than in the control group (P< 0·05). In vitro studies showed that incubation of cholesterol-loaded J774A.1 macrophages with 9-cis-RA (0·1, 1 and 10 μmol/l) induced cholesterol efflux in a dose-dependent manner. The 9-cis-RA treatment markedly attenuated lipid accumulation in macrophages exposed to oxidised LDL. Moreover, treatment with 9-cis-RA significantly increased the protein expression levels of ABCA1 and ABCG1 in J774A.1 macrophages in a dose-dependent manner. Furthermore, 9-cis-RA dose-dependently enhanced the protein expression level of liver X receptor-α (LXRα), the upstream regulator of ABCA1 and ABCG1. Taken together, the present results show that 9-cis-RA suppresses foam cell formation and prevents HFD-induced atherogenesis via the LXRα-dependent up-regulation of ABCA1 and ABCG1.