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

• Published in: PloS one Vol. 8; no. 6; p. e66876
• Main Authors: Hu, Yan-Wei, Ma, Xin, Huang, Jin-Lan, Mao, Xin-Ru, Yang, Jun-Yao, Zhao, Jia-Yi, Li, Shu-Fen, Qiu, Yu-Rong, Yang, Jia, Zheng, Lei, Wang, Qian
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.06.2013; Public Library of Science (PLoS)
• Subjects: ABCA1 protein; Animals; Apolipoprotein E; Apolipoproteins E - deficiency; Arteriosclerosis; Atherosclerosis; ATP-binding protein; Autophagy; Biology; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Cardiovascular disease; Cardiovascular diseases; CD36 antigen; Cell Line; Chemical compounds; Cholesterol; Cholesterol, Dietary - adverse effects; Cholesterol, Dietary - blood; Cytokines - blood; Diet; Diet, High-Fat - adverse effects; Efflux; Foam; Foams; Gene expression; Gene Expression Regulation - drug effects; High density lipoprotein; Hospitals; Humans; Inflammation; Interleukin 6; Laboratory animals; Lipids; Lipoprotein (low density) receptors; Lipoproteins; Lipoproteins (high density); Lipoproteins (low density); Lipoproteins (very low density); Liver - drug effects; Liver - metabolism; Liver X Receptors - metabolism; Low density lipoprotein; Macrophages; Male; Medicine; Metabolism; Mice; Mice, Inbred C57BL; Morbidity; Npc1 protein; Pharmacology; Physiological effects; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Plaque, Atherosclerotic - prevention & control; Plasma levels; PPAR gamma - metabolism; Proteins; Rodents; Signal Transduction - drug effects; siRNA; Tumor necrosis factor-α
• DOI: 10.1371/journal.pone.0066876
• ISSN: 1932-6203

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. 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-1β, IL-6, TNF-α 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 LXRα siRNA and PPARγ 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 PPARγ siRNA made the DHC-induced up-regulation of LXRα expression notably abolished while treatment with LXRα siRNA had no effect on DHC-induced PPARγ expression. These observations provide direct evidence that DHC can significantly decrease atherosclerotic plaque formation involving in a PPARγ/LXRα pathway and thus DHC may represent a promising candidate for a therapeutic agent for the treatment or prevention of atherosclerosis.