Cardiovasc Res 2011 Dec;92 (3): 504-13. [IF:6.051]
Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis.
Ma L , Zhong J , Zhao Z , Luo Z , Ma S , Sun J , He H , Zhu T , Liu D , Zhu Z , Tepel M .
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, People' s Republic of China.
第三军医大学大坪医院高血压内分泌科，第三军医大学高血压及代谢病中心，重庆市高血压研究所
Abstract
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.
摘要：
瞬时受体电位香草酸亚型1(TRPV1)通道的激活可能引起脂质的积累和细胞的炎症反应。现在我们证实了一个假说，那就是TRPV1通道的激活可以减轻在高脂饮食下敲除载脂蛋白E（ApoE）的小鼠而不是同时敲除TRPV1和ApoE的小鼠的动脉粥样硬化。我们利用RT-PCR、免疫印迹和免疫组化的方法检测了血管平滑肌细胞(VSMC)和C57BL/6J小鼠主动脉中TRPV1的mRNA和蛋白表达。在体外我们发现在特异性的TRPV1激动剂辣椒素和超强辣素可以剂量依赖性的增加细胞内钙离子的浓度并且显著性地降低脂质在C57BL/6J 小鼠而不是敲除TRPV1小鼠的血管平滑肌细胞中的积累。在血管平滑肌中，TRPV1的激活通过钙离子依赖以及钙调神经磷酸酶和蛋白激酶A依赖途径增加了ATP结合盒转运子A1(ABCA1)的表达，同时也减少了低密度脂蛋白受体相关蛋白1 (LRP1)的表达。以上结果表明激活TRPV1可以增加血管平滑肌细胞内胆固醇的外派并且降低其胆固醇的摄取。给予高脂饮食喂养的敲除ApoE的小鼠辣椒素24周，长时间激活TRPV1可以增加ABCA1并减少LRP1在主动脉中的表达。在高脂饮食喂养的敲除ApoE的小鼠而不是同时敲除TRPV1和ApoE的小鼠中，长时间激活TRPV1可以显著性地降低脂质的积累和主动脉窦和胸腹大动脉中动脉粥样硬化斑块的数量。这些结果揭示激活TRPV1能改善高脂饮食诱导的动脉粥样硬化，也暗示激活TRPV1可能作为减轻高脂饮食诱导的动脉粥样硬化的一个新的治疗手段。
