Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary...

Area of Science:

• Cardiovascular Research
• Endocrinology
• Pulmonary Medicine

Background:

• Pulmonary arterial hypertension (PAH) involves reduced nitric oxide (NO) and increased endothelin-1.
• Endothelin-1 signaling via endothelin-B receptor (ET(B)) and endothelial nitric oxide synthase (eNOS) is perturbed in PAH.
• Aldosterone, stimulated by endothelin-1, causes vascular dysfunction by increasing oxidative stress and decreasing NO.

Purpose of the Study:

• To investigate the hypothesis that aldosterone modulates PAH by disrupting ET(B)-eNOS signaling through pulmonary endothelial oxidant stress.
• To elucidate the role of aldosterone in the pathogenesis of PAH.

Main Methods:

• Examined plasma and lung aldosterone levels, and NO metabolites in rats with PAH.
• Investigated endothelin-1-induced aldosterone synthesis in human pulmonary artery endothelial cells (PAECs).
• Assessed the effect of aldosterone on reactive oxygen species (ROS) production and eNOS activity in PAECs.
• Utilized site-directed mutagenesis (ET(B)-Cys405Ala) to confirm the role of a specific thiol in ET(B)-eNOS signaling.
• Evaluated the effects of mineralocorticoid receptor antagonists (spironolactone, eplerenone) on ROS, NO production, vascular remodeling, and hemodynamics in vitro and in vivo PAH models.

Main Results:

• Elevated endothelin-1 in PAH rats correlated with increased aldosterone and decreased lung NO metabolites.
• Endothelin-1 upregulated aldosterone synthase in PAECs, increasing aldosterone levels.
• Aldosterone increased ROS production, oxidatively modified ET(B) cysteinyl thiols (Cys405), and decreased endothelin-1-stimulated eNOS activity.
• ET(B)-Cys405Ala mutation rescued NO synthesis under oxidant stress, confirming Cys405 as a critical redox-sensitive site.
• Spironolactone in PAECs restored ET(B)-dependent NO production by reducing aldosterone-mediated ROS.
• Spironolactone and eplerenone prevented or reversed pulmonary vascular remodeling and improved hemodynamics in vivo PAH models.

Conclusions:

• Aldosterone acts via an ET(B) cysteinyl thiol redox switch to reduce pulmonary endothelium-derived NO, thereby promoting PAH.
• Targeting the aldosterone-ET(B)-eNOS pathway with mineralocorticoid receptor antagonists represents a potential therapeutic strategy for PAH.