resiniferatoxin and Aortic-Diseases

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.. 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.. Activation of TRPV1 may be a novel therapeutic tool to attenuate atherosclerosis caused by a high-fat diet.

Topics: Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Blotting, Western; Calcineurin; Calcium; Capsaicin; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Dietary Fats; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Immunohistochemistry; Lipid Metabolism; Low Density Lipoprotein Receptor-Related Protein-1; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Polymerase Chain Reaction; Receptors, LDL; RNA, Messenger; Time Factors; TRPV Cation Channels; Tumor Suppressor Proteins