Kasahara Takeru, Ogata Takehiro, Nakanishi Naohiko, Tomita Shinya, Higuchi Yusuke, Maruyama Naoki, Hamaoka Tetsuro, Matoba Satoaki
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Department of Pathology and Cell Regulation, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Heliyon. 2023 Jun 11;9(6):e17193. doi: 10.1016/j.heliyon.2023.e17193. eCollection 2023 Jun.
Pulmonary hypertension (PH) is associated with a poor prognosis even in recent years. Caveolin-1 (CAV1), a caveolae-associated protein, is a causal gene in PH. Cavin-2, one of the other caveolae-associated proteins, forms protein complexes with CAV1 and influences each other's functions. However, the role of Cavin-2 in PH has not been thoroughly investigated. To clarify the role of Cavin-2 in PH, we exposed Cavin-2-deficient (Cavin-2 KO) mice to hypoxia. A part of the analyses was confirmed in human pulmonary endothelial cells (HPAECs). After 4-week 10% O hypoxic exposure, we performed physiological, histological, and immunoblotting analyses. Right ventricular (RV) systolic pressure elevation and RV hypertrophy were exacerbated in Cavin-2 KO mice with hypoxia-induced PH (Cavin-2 KO PH mice). The vascular wall thickness of pulmonary arterioles was aggravated in Cavin-2 KO PH mice. Cavin-2 loss reduced CAV1 and induced sustained endothelial nitric oxide synthase (eNOS) hyperphosphorylation in the Cavin-2 KO PH lungs and HPAECs. NOx production associated with eNOS phosphorylation was also increased in the Cavin-2 KO PH lung and HPAECs. Furthermore, the nitration of proteins, including protein kinase G (PKG), was raised in the Cavin-2 KO PH lungs. In conclusion, we revealed that Cavin-2 loss exacerbated hypoxia-induced PH. Our results suggest that Cavin-2 loss leads to sustained eNOS hyperphosphorylation in pulmonary artery endothelial cells via CAV1 reduction, resulting in Nox overproduction-mediated nitration of proteins, including PKG, in smooth muscle cells.
即使在近年来，肺动脉高压（PH）仍与不良预后相关。小窝蛋白-1（CAV1）是一种与小窝相关的蛋白质，是PH中的一个致病基因。Cavin-2是另一种与小窝相关的蛋白质，它与CAV1形成蛋白质复合物并相互影响彼此的功能。然而，Cavin-2在PH中的作用尚未得到充分研究。为了阐明Cavin-2在PH中的作用，我们将Cavin-2基因敲除（Cavin-2 KO）小鼠暴露于低氧环境中。部分分析在人肺内皮细胞（HPAECs）中得到了证实。在进行4周10%氧气的低氧暴露后，我们进行了生理、组织学和免疫印迹分析。在低氧诱导的PH的Cavin-2 KO小鼠（Cavin-2 KO PH小鼠）中，右心室（RV）收缩压升高和RV肥大加剧。Cavin-2 KO PH小鼠的肺小动脉血管壁厚度增加。Cavin-2缺失降低了CAV1，并在Cavin-2 KO PH肺组织和HPAECs中诱导了内皮型一氧化氮合酶（eNOS）的持续高磷酸化。与eNOS磷酸化相关的NOx生成在Cavin-2 KO PH肺组织和HPAECs中也增加。此外，包括蛋白激酶G（PKG）在内的蛋白质硝化作用在Cavin-2 KO PH肺组织中升高。总之，我们发现Cavin-2缺失加剧了低氧诱导的PH。我们的结果表明，Cavin-2缺失通过CAV1减少导致肺动脉内皮细胞中eNOS持续高磷酸化，从而导致平滑肌细胞中包括PKG在内的蛋白质的Nox过量生成介导的硝化作用。
