WIN55212-2 ameliorates atherosclerosis associated with suppression of pro-inflammatory responses in ApoE-knockout mice

The role of inflammation in all stages of atherosclerosis has been actively investigated, with an emphasis on the discovery of novel and innovative drugs for treatment and prevention. The anti-inflammatory and immunomodulatory capacity of cannabinoids are well established, and these agents have a broad therapeutic potential in various inflammatory diseases, including cardiovascular diseases. The aim of this study was to investigate the effect of WIN55212-2, a synthetic cannabinoid, on atherosclerosis using the apolipoprotein E-knockout (ApoE^-/-) mouse on a cholate-containing high-fat diet. Our results showed that WIN55212-2 reduced the size of atherosclerotic lesions in the aorta root, and did not affect serum lipid levels significantly. Furthermore, alleviation of atherosclerosis by WIN55212-2 was associated with a smaller content of macrophages in plaque lesion as well as decreasing pro-inflammatory gene expression and NF-κB activation in aortic tissues. Oxidized LDL (ox-LDL) dramatically induced NF-κB activation, and enhanced pro-inflammatory mRNA and protein expression in peritoneal macrophages isolated from ApoE^-/- mice. It is noteworthy that all of the above-mentioned effects of ox-LDL were attenuated by WIN55212-2. Moreover, WIN55212-2 also attenuated the inflammatory response that LPS induced. AM630, a cannabinoid receptor 2 (CB₂) special antagonist completely abolished the protective effects of WIN55212-2 both in vivo and in vitro. Our data provide strong evidence that WIN55212-2 can potentially inhibit atherosclerosis in ApoE^-/- mice. Importantly, all the beneficial effects of WIN55212-2 in our model were closely associated with the suppression of pro-inflammatory responses and were mediated by the CB₂ receptor.