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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Abstract
Background—: 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 (ET B ), 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 generation and decreasing NO · levels. We hypothesized that aldosterone modulates PAH by disrupting ET B -eNOS signaling through a mechanism involving increased pulmonary endothelial oxidant stress. Methods and Results—: 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-sided heart failure. In human pulmonary artery endothelial cells, endothelin-1 increased aldosterone levels via peroxisome proliferator-activated receptor gamma coactivator-1α/steroidogenesis factor-1–dependent upregulation of aldosterone synthase. Aldosterone also increased reactive oxygen species production, which oxidatively modified cysteinyl thiols in the eNOS-activating region of ET B to decrease endothelin-1–stimulated eNOS activity. Substitution of ET B -Cys405 with alanine improved ET B -dependent NO · synthesis under conditions of oxidant stress, confirming that Cys405 is a redox-sensitive thiol that is necessary for ET B -eNOS signaling. In human pulmonary artery endothelial cells, mineralocorticoid receptor antagonism with spironolactone decreased aldosterone-mediated reactive oxygen species generation and restored ET B -dependent NO · production. Spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in 2 animal models of PAH in vivo. Conclusions—: Our findings demonstrate that aldosterone modulates an ET B cysteinyl thiol redox switch to decrease pulmonary endothelium-derived NO · and promote PAH.

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