Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and Modulate Pulmonary Arterial Hypertension

• Published in: Circulation (New York, N.Y.) N.Y.), 2012-08, Vol.126 (8), p.963-974
• Main Authors: MARON, Bradley A, ZHANG, Ying-Yi, WHITE, Kevin, CHAN, Stephen Y, HANDY, Diane E, MAHONEY, Christopher E, LOSCALZO, Joseph, LEOPOLD, Jane A
• Format: Article
• Language: English
• Subjects: Aldosterone - metabolism; Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Cysteine - metabolism; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelin-1 - metabolism; Endothelin-1 - pharmacology; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Male; Medical sciences; Mineralocorticoid Receptor Antagonists - pharmacology; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Oxidation-Reduction; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pneumology; Pulmonary Artery - cytology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Pulmonary Wedge Pressure - drug effects; Pulmonary Wedge Pressure - physiology; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B - metabolism; Spironolactone - pharmacology; Sulfhydryl Compounds - metabolism
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.112.094722

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. 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. Our findings demonstrate that aldosterone modulates an ET(B) cysteinyl thiol redox switch to decrease pulmonary endothelium-derived NO(·) and promote PAH.