Dihydrocapsaicin Attenuates Plaque Formation through a PPARγ/LXRα Pathway in apoE-/- Mice Fed a High-Fat/High-Cholesterol Diet

Aims: Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. There is evidence that dihydrocapsaicin (DHC) can exert multiple pharmacological and physiological effects. Here, we explored the effect of DHC in atherosclerotic plaque progression in apoE(-/-) mice fed a high-fat/high-cholesterol diet. Methods and Results: apoE(-/-) mice were randomly divided into two groups and fed a high-fat/high-cholesterol diet with or without DHC for 12 weeks. We demonstrated that cellular cholesterol content was significantly decreased while apoA1-mediated cholesterol efflux was significantly increased following treatment with DHC in THP-1 macrophage-derived foam cells. We also observed that plasma levels of TG, LDL-C, VLDL-C, IL-1 beta, IL-6, TNF-alpha and CRP were markedly decreased while plasma levels of apoA1 and HDL-C were significantly increased, and consistent with this, atherosclerotic lesion development was significantly inhibited by DHC treatment of apoE(-/-) mice fed a high-fat/high-cholesterol diet. Moreover, treatment with both LXR alpha siRNA and PPAR gamma siRNA made the up-regulation of DHC on ABCA1, ABCG1, ABCG5, SR-B1, NPC1, CD36, LDLR, HMGCR, apoA1 and apoE expression notably abolished while made the down-regulation of DHC on SRA1 expression markedly compensated. And treatment with PPAR gamma siRNA made the DHC-induced up-regulation of LXR alpha expression notably abolished while treatment with LXR alpha siRNA had no effect on DHC-induced PPAR gamma expression. Conclusion: These observations provide direct evidence that DHC can significantly decrease atherosclerotic plaque formation involving in a PPAR gamma/LXR alpha pathway and thus DHC may represent a promising candidate for a therapeutic agent for the treatment or prevention of atherosclerosis.