Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis

Aims Activation of transient receptor potential vanilloid type-1 (TRPV1) channels may affect lipid storage and the cellular inflammatory response. Now, we tested the hypothesis that activation of TRPV1 channels attenuates atherosclerosis in apolipoprotein E knockout mice (ApoE−/−) but not ApoE−/−TRPV1−/− double knockout mice on a high-fat diet. Methods and results Both TRPV1 mRNA and protein expression were identified in vascular smooth muscle cells (VSMC) and in aorta from C57BL/6J mice using RT–PCR, immunoblotting, and immunohistochemistry. In vitro , activation of TRPV1 by the specific agonists capsaicin and resiniferatoxin dose-dependently increased cytosolic calcium and significantly reduced the accumulation of lipids in VSMC from C57BL/6J mice but not from TRPV1−/− mice. TRPV1 activation increased ATP-binding cassette transporter A1 (ABCA1) expression and reduced low-density lipoprotein-related protein 1 (LRP1) expression in VSMC by calcium-dependent and calcineurin- and protein kinase A-dependent mechanisms. These results showed increased cellular cholesterol efflux and reduced cholesterol uptake. In vivo , long-term activation of TRPV1 by capsaicin for 24 weeks increased ABCA1 and reduced LRP1 expression in aorta from ApoE−/− mice on a high-fat diet. Long-term activation of TRPV1 significantly reduced lipid storage and atherosclerotic lesions in the aortic sinus and in the thoracoabdominal aorta from ApoE−/− mice but not from ApoE−/−TRPV1−/− mice on a high-fat diet. These findings indicated that TRPV1 activation ameliorates high-fat diet-induced atherosclerosis. Conclusion Activation of TRPV1 may be a novel therapeutic tool to attenuate atherosclerosis caused by a high-fat diet.