NADPH oxidase 4 contributes to TRPV4-mediated endothelium-dependent vasodilation in human arterioles by regulating protein phosphorylation of TRPV4 channels.
NADPH oxidase 4 contributes to TRPV4-mediated endothelium-dependent vasodilation in human arterioles by regulating protein phosphorylation of TRPV4 channels.
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DOI：
10.1007/s00395-022-00932-9
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发表时间：
2022-04-25
影响因子：
9.5
通讯作者：
中科院分区：
文献类型：
--
作者：
内皮依赖性血管舒张功能受损已被认为是冠状动脉微血管功能障碍（CMD）的关键组成部分。更好地了解血管舒张在人体小动脉的内皮途径可能会提供新的见解CMD的机制。研究TRPV 4、NOX 4在人小动脉中的作用及其相互作用，并探讨其潜在机制。从71例无冠状动脉疾病患者的脂肪和心脏组织中新鲜分离小动脉，并通过视频显微镜研究血管反应性。在人脂肪小动脉（HAA）中，TRPV 4抑制剂HC 067047和NOX 1/4抑制剂GKT 137831显著降低了ACh诱导的扩张，但GKT 137831在TRPV 4抑制剂存在下没有进一步影响扩张。GKT 137831还抑制TRPV 4激动剂GSK 1016790 A诱导的HAA和人冠状小动脉（HCA）扩张。在HAA和HCA的内皮细胞中检测到NOX 4的转录和蛋白。使用fura-2成像，GKT 137831显著降低内皮细胞和TRPV 4-WT过表达人冠状动脉内皮细胞（HCAEC）原代培养物中GSK 1016790 A诱导的Ca 2+内流。然而，GKT 137831不影响非磷酸化TRPV 4-S823 A/S824 A过表达HCAEC中TRPV 4介导的Ca 2+内流。此外，用GKT 137831处理HCAEC降低了TRPV 4中Ser 824的磷酸化水平。最后，邻位连接试验（PLA）揭示了NOX 4和TRPV 4蛋白的共定位。TRPV 4和NOX 4都有助于无冠状动脉疾病患者的ACh诱导的人小动脉扩张。NOX 4增加内皮细胞中TRPV 4的磷酸化，这反过来又增强TRPV 4介导的Ca 2+内流和随后的人小动脉中的内皮依赖性扩张。
Impaired endothelium-dependent vasodilation has been suggested to be a key component of coronary microvascular dysfunction (CMD). A better understanding of endothelial pathways involved in vasodilation in human arterioles may provide new insight into the mechanisms of CMD. To investigate the role of TRPV4, NOX4, and their interaction in human arterioles and examine the underlying mechanisms. Arterioles were freshly isolated from adipose and heart tissues obtained from 71 patients without coronary artery disease, and vascular reactivity was studied by videomicroscopy. In human adipose arterioles (HAA), ACh-induced dilation was significantly reduced by TRPV4 inhibitor HC067047 and by NOX 1/4 inhibitor GKT137831, but GKT137831 did not further affect the dilation in the presence of TRPV4 inhibitors. GKT137831 also inhibited TRPV4 agonist GSK1016790A-induced dilation in HAA and human coronary arterioles (HCA). NOX4 transcripts and proteins were detected in endothelial cells of HAA and HCA. Using fura-2 imaging, GKT137831 significantly reduced GSK1016790A-induced Ca2+ influx in the primary culture of endothelial cells and TRPV4-WT-overexpressing human coronary artery endothelial cells (HCAEC). However, GKT137831 did not affect TRPV4-mediated Ca2+ influx in non-phosphorylatable TRPV4-S823A/S824A-overexpressing HCAEC. In addition, treatment of HCAEC with GKT137831 decreased the phosphorylation level of Ser824 in TRPV4. Finally, proximity ligation assay (PLA) revealed co-localization of NOX4 and TRPV4 proteins. Both TRPV4 and NOX4 contribute to ACh-induced dilation in human arterioles from patients without coronary artery disease. NOX4 increases TRPV4 phosphorylation in endothelial cells, which in turn enhances TRPV4-mediated Ca2+ entry and subsequent endothelium-dependent dilation in human arterioles.
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影响因子：
7.4
作者：
Djordjevic, T;Pogrebniak, A;Görlach, A
通讯作者：
Görlach, A
DOI：
10.1152/ajpheart.00717.2011
发表时间：
2012-02-01
影响因子：
4.8
作者：
Bubolz, Aaron H.;Mendoza, Suelhem A.;Zhang, David X.
通讯作者：
Zhang, David X.
DOI：
10.1152/ajpheart.00142.2011
发表时间：
2011-09-01
影响因子：
4.8
作者：
Adapala, Ravi K.;Talasila, Phani K.;Thodeti, Charles K.
通讯作者：
Thodeti, Charles K.
影响因子：
7.3
作者：
Buus, NH;Simonsen, U;Mulvaney, NJ
通讯作者：
Mulvaney, NJ
影响因子：
6.6
作者：
Hirano, Kazufumi;Chen, Woei Shin;Rutter, A. Richard
通讯作者：
Rutter, A. Richard