Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension
Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension
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DOI：
10.1073/pnas.2023130118
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发表时间：
2021-04-27
影响因子：
11.1
通讯作者：
Sonkusare, Swapnil K.
中科院分区：
文献类型：
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作者：
Daneva, Zdravka;Marziano, Corina;Sonkusare, Swapnil K.
最近的研究集中在毛细血管内皮TRPV 4通道对肺病理学的贡献，包括肺水肿和肺损伤。然而，在肺动脉高压（PH）中，小肺动脉是病理学的焦点，而这一关键解剖结构中的内皮TRPV 4通道在PH中仍未被探索。在这里，我们提供了证据表明，内皮细胞小窝中的TRPV 4通道维持较低的肺动脉压力在正常条件下。此外，在PH小鼠模型和PH患者的肺动脉中，小窝TRPV 4通道的活性受损。在PH中，内皮细胞小窝处的iNOS和NOX 1酶的上调导致氧化剂分子过氧亚硝酸盐的形成。过氧亚硝酸盐反过来又靶向结构蛋白小窝蛋白-1以降低TRPV 4通道的活性。这些结果表明，内皮小窝1？TRPV 4通道信号降低肺动脉压，内皮小窝蛋白-1受损？TRPV 4通道信号有助于PH中肺动脉压升高。因此，抑制NOX 1或iNOS活性，或降低内皮过氧亚硝酸盐水平，可能代表PH中恢复血管舒张和肺动脉压的策略。
Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin1?TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1?TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.