Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter 1
-
ATP-Binding Cassette Transporters / metabolism
-
Animals
-
Aorta / drug effects
-
Aorta / metabolism
-
Aortic Diseases / genetics
-
Aortic Diseases / metabolism
-
Aortic Diseases / pathology
-
Aortic Diseases / prevention & control*
-
Apolipoproteins E / genetics
-
Apolipoproteins E / metabolism
-
Atherosclerosis / genetics
-
Atherosclerosis / metabolism
-
Atherosclerosis / pathology
-
Atherosclerosis / prevention & control*
-
Blotting, Western
-
Calcineurin / metabolism
-
Calcium / metabolism
-
Capsaicin / pharmacology*
-
Cells, Cultured
-
Cyclic AMP-Dependent Protein Kinases / metabolism
-
Dietary Fats / administration & dosage
-
Dietary Fats / metabolism*
-
Disease Models, Animal
-
Diterpenes / pharmacology*
-
Dose-Response Relationship, Drug
-
Immunohistochemistry
-
Lipid Metabolism / drug effects
-
Low Density Lipoprotein Receptor-Related Protein-1
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Muscle, Smooth, Vascular / drug effects
-
Muscle, Smooth, Vascular / metabolism
-
Myocytes, Smooth Muscle / drug effects
-
Myocytes, Smooth Muscle / metabolism
-
Polymerase Chain Reaction
-
RNA, Messenger / metabolism
-
Receptors, LDL / metabolism
-
TRPV Cation Channels / agonists*
-
TRPV Cation Channels / deficiency
-
TRPV Cation Channels / genetics
-
TRPV Cation Channels / metabolism
-
Time Factors
-
Tumor Suppressor Proteins / metabolism
Substances
-
ATP Binding Cassette Transporter 1
-
ATP-Binding Cassette Transporters
-
Apolipoproteins E
-
Dietary Fats
-
Diterpenes
-
Low Density Lipoprotein Receptor-Related Protein-1
-
Lrp1 protein, mouse
-
RNA, Messenger
-
Receptors, LDL
-
TRPV Cation Channels
-
TRPV1 protein, mouse
-
Tumor Suppressor Proteins
-
resiniferatoxin
-
Cyclic AMP-Dependent Protein Kinases
-
Calcineurin
-
Capsaicin
-
Calcium