Activation of endothelial TRPV4 channels mediates flow- induced dilation in human coronary arterioles: role of Ca2+ entry and mitochondrial ROS signaling
Activation of endothelial TRPV4 channels mediates flow- induced dilation in human coronary arterioles: role of Ca2+ entry and mitochondrial ROS signaling
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DOI：
10.1152/ajpheart.00717.2011
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发表时间：
2012-02-01
影响因子：
4.8
通讯作者：
Zhang, David X.
中科院分区：
文献类型：
--
作者：
Bubolz, Aaron H.;Mendoza, Suelhem A.;Zhang, David X.
Bubolz AH，门多萨SA，Zheng X，Zinkevich NS，Li R，Gutterman DD，Zhang DX.内皮TRPV 4通道的激活介导人冠状小动脉中流动诱导的扩张：Ca 2+进入和线粒体ROS信号传导的作用Am J Physiol Heart Circ Physiol 302：H634-H642，2012.首次发表于2011年12月2日; doi：10.1152/ajpheart.00717.2011。在冠状动脉疾病患者的冠状动脉（HCA）中，血流诱导的扩张是由一种独特的机制介导的，该机制涉及内皮细胞（EC）线粒体释放H2 O2。流动如何激活EC引起线粒体释放H2 O2仍不清楚。在这里，我们研究了瞬时受体电位香草酸4型（TRPV 4）通道，机械敏感性Ca 2+渗透性阳离子通道，在介导ROS的形成和流动诱导的扩张HCAs的作用。采用RT-PCR、Western blot和免疫组织化学方法检测HCAs和培养的人冠状动脉内皮细胞（HCAECs）中TRPV 4通道的mRNA和蛋白表达。在HCAEC中，选择性TRPV 4激动剂4 α-佛波醇-12，13-二癸酸酯（4 α-PDD）显著增加（通过Ca 2+内流）细胞内Ca 2+浓度。在分离的HCA中，4 α-PDD激活TRPV 4通道导致有效的浓度依赖性扩张，并且通过去除内皮和过氧化氢酶（一种H2 O2代谢酶）抑制扩张。荧光活性氧测定显示，4 α-PDD增加了HCAEC线粒体超氧化物的产生。4 α-PDD还增强HCAs中H2 O2和超氧化物的产生。最后，我们发现，不同的TRPV 4拮抗剂和TRPV 4特异性小干扰RNA显着抑制流动诱导的扩张的HCAs。总之，内皮TRPV 4通道在HCA的流动介导的扩张中起关键作用。TRPV 4介导的Ca 2+内流可能是导致HCAs中线粒体ROS释放的重要信号事件。阐明这种新的TRPV 4-ROS通路可能会提高我们对冠状动脉疾病和/或其他心血管疾病发病机制的理解。
Bubolz AH, Mendoza SA, Zheng X, Zinkevich NS, Li R, Gutterman DD, Zhang DX. Activation of endothelial TRPV4 channels mediates flow-induced dilation in human coronary arterioles: role of Ca2+ entry and mitochondrial ROS signaling. Am J Physiol Heart Circ Physiol 302: H634-H642, 2012. First published December 2, 2011; doi:10.1152/ajpheart.00717.2011.-In human coronary arterioles (HCAs) from patients with coronary artery disease, flow-induced dilation is mediated by a unique mechanism involving the release of H2O2 from the mitochondria of endothelial cells (ECs). How flow activates ECs to elicit the mitochondrial release of H2O2 remains unclear. Here, we examined the role of the transient receptor potential vanilloid type 4 (TRPV4) channel, a mechanosensitive Ca2+-permeable cation channel, in mediating ROS formation and flow-induced dilation in HCAs. Using RT-PCR, Western blot analysis, and immunohistochemical analysis, we detected the mRNA and protein expression of TRPV4 channels in ECs of HCAs and cultured human coronary artery ECs (HCAECs). In HCAECs, 4 alpha-phorbol-12,13-didecanoate (4 alpha-PDD), a selective TRPV4 agonist, markedly increased (via Ca2+ influx) intracellular Ca2+ concentration. In isolated HCAs, activation of TRPV4 channels by 4 alpha-PDD resulted in a potent concentration-dependent dilation, and the dilation was inhibited by removal of the endothelium and by catalase, a H2O2-metabolizing enzyme. Fluorescence ROS assays showed that 4 alpha-PDD increased the production of mitochondrial superoxide in HCAECs. 4 alpha-PDD also enhanced the production of H2O2 and superoxide in HCAs. Finally, we found that flow-induced dilation of HCAs was markedly inhibited by different TRPV4 antagonists and TRPV4-specific small interfering RNA. In conclusion, the endothelial TRPV4 channel is critically involved in flow-mediated dilation of HCAs. TRPV4-mediated Ca2+ entry may be an important signaling event leading to the flow-induced release of mitochondrial ROS in HCAs. Elucidation of this novel TRPV4-ROS pathway may improve our understanding of the pathogenesis of coronary artery disease and/or other cardiovascular disorders.