Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension.
Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension.
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DOI：
10.1161/circulationaha.112.094722
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发表时间：
2012-08-21
期刊：
影响因子：
37.8
通讯作者：
Leopold JA
中科院分区：
文献类型：
--
作者：
Maron BA;Zhang YY;White K;Chan SY;Handy DE;Mahoney CE;Loscalzo J;Leopold JA
肺动脉高压（PAH）的部分特征是内皮细胞一氧化氮（NO·）生成减少和内皮素-1水平升高。已知内皮素-1通过内皮素B受体（ETB）刺激内皮一氧化氮合酶（eNOS），这表明该信号通路在PAH中受到干扰。内皮素-1还刺激肾上腺醛固酮合成;在全身血管中，醛固酮增多症通过增加内皮活性氧（ROS）生成和降低NO·水平诱导血管功能障碍。我们假设醛固酮通过增加肺内皮氧化应激的机制干扰ETB-eNOS信号传导来调节PAH。在PAH大鼠中，血浆和肺组织中内皮素-1水平升高与醛固酮水平升高相关，而在没有左心衰的情况下，肺NO·代谢产物减少。在人肺动脉内皮细胞（HPAECs）中，内皮素-1通过PGC-1α/类固醇生成因子-1依赖性上调醛固酮合成酶增加醛固酮水平。醛固酮还增加ROS的产生，其氧化修饰ETB的eNOS激活区域中的半胱氨酰硫醇以降低内皮素-1刺激的eNOS活性。用丙氨酸取代ETB-Cys 405改善了氧化应激条件下ETB依赖的NO·合成，证实Cys 405是ETB-eNOS信号传导所必需的氧化还原敏感性硫醇。在HPAECs中，盐皮质激素受体拮抗剂螺内酯减少了醛固酮介导的ROS产生，并恢复了ETB依赖的NO·产生。螺内酯或依普利酮预防或逆转肺血管重构，并改善两种PAH动物模型体内心肺血流动力学。我们的研究结果表明，醛固酮调节ETB半胱氨酰巯基氧化还原开关，以减少肺内皮源性NO·和促进PAH。
Pulmonary arterial hypertension (PAH) is characterized, in part, by decreased endothelial nitric oxide (NO•) production and elevated levels of endothelin-1. Endothelin-1 is known to stimulate endothelial nitric oxide synthase (eNOS) via the endothelin-B receptor (ETB), suggesting that this signaling pathway is perturbed in PAH. Endothelin-1 also stimulates adrenal aldosterone synthesis; in systemic blood vessels, hyperaldosteronism induces vascular dysfunction by increasing endothelial reactive oxygen species (ROS) generation and decreasing NO• levels. We hypothesized that aldosterone modulates PAH by disrupting ETB-eNOS signaling through a mechanism involving increased pulmonary endothelial oxidant stress. In rats with PAH, elevated endothelin-1 levels were associated with elevated aldosterone levels in plasma and lung tissue and decreased lung NO• metabolites in the absence of left heart failure. In human pulmonary artery endothelial cells (HPAECs), endothelin-1 increased aldosterone levels via PGC-1α/steroidogenesis factor-1-dependent upregulation of aldosterone synthase. Aldosterone also increased ROS production, which oxidatively modified cysteinyl thiols in the eNOS-activating region of ETB to decrease endothelin-1-stimulated eNOS activity. Substitution of ETB-Cys405 with alanine improved ETB-dependent NO• synthesis under conditions of oxidant stress, confirming that Cys405 is a redox sensitive thiol that is necessary for ETB-eNOS signaling. In HPAECs, mineralocorticoid receptor antagonism with spironolactone decreased aldosterone-mediated ROS generation and restored ETB-dependent NO• production. Spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in two animal models of PAH in vivo. Our findings demonstrate that aldosterone modulates an ETB cysteinyl thiol redox switch to decrease pulmonary endothelium-derived NO• and promote PAH.