Figure 7.

A proposed mechanism by which hyperaldosteronism decreases pulmonary endothelial eNOS activation and nitric oxide (NO•) generation in PAH. Hyperaldosteronism (ALDO) in pulmonary arterial hypertension (PAH) may occur via i) endothelin-1 (ET-1)-mediated activation of PPARγ coactivator-1α (PGC-1α)/steroidogenesis factor-1 (SF) to increase CYP11B2 (aldosterone synthase) gene transcription in human pulmonary artery endothelial cells (HPAECs); ii) hypoxia-stimulated upregulation of steroidogenic acute regulatory protein (StAR) by increasing binding of c-fos and c-jun to the promoter; and, iii) adrenal ALDO synthesis via ET-1 and/or overactivation of the renin-angiotensin pathway. Stimulation of the mineralocorticoid receptor (MR) in HPAECs by ALDO activates NADPH oxidase type 4 (NOX4) to increase levels of hydrogen peroxide (H₂O₂), which, in turn, oxidatively modifies redox sensitive, functional cysteinyl thiol(s) in the ET_B receptor (Cys405) to impair ET_B-dependent activation of eNOS and decrease synthesis of nitric oxide (NO^•). eNOS, endothelial nitric oxide synthase; R-SO_XH, higher oxidative intermediaries of cysteine. Adapted from ref 9.