Salusin-α Restores Vascular Relaxation and Remodeling in Pulmonary Hypertension

BACKGROUND: A hallmark of pulmonary hypertension (PH) is the progressive increase in pulmonary arterial resistance caused by impaired pulmonary artery (PA) relaxation and vascular remodeling. Salusin-α, a cardiovascular-active peptide, has been implicated in several cardiovascular diseases; however, its role in PH remains undefined. METHODS: PAs were isolated from rats for isometric tension recording to assess relaxation. PA remodeling was quantified using histological morphometric analysis. Right ventricular pressure and hypertrophy were measured to evaluate PH severity. RESULTS: Salusin-α levels were significantly decreased in both plasma and PAs from PH rats compared with controls. Both acute and chronic salusin-α administration improved endothelium-dependent and -independent PA relaxation, increased endothelial nitric oxide synthase activity and nitric oxide levels in PA endothelial cells, enhanced Nrf2 (nuclear factor erythroid 2-related factor 2) and superoxide dismutase expression and activity in PA smooth muscle cells, and decreased NAD(P)H oxidase expression, activity, and reactive oxygen species levels. Salusin-α also inhibited PA smooth muscle cell proliferation and migration, attenuated pulmonary vascular remodeling, and decreased right ventricular pressure, hypertrophy, and mortality in PH rats. Neutralizing endogenous salusin-α exerted opposite effects. Pharmacological inhibition demonstrated that endothelial nitric oxide synthase and superoxide dismutase contributed to the protective actions of salusin-α, whereas NAD(P)H oxidase inhibition or reactive oxygen species scavenging prevented the effects of salusin-α neutralization. CONCLUSIONS: Salusin-α improves endothelium-dependent vasodilation via endothelial nitric oxide synthase mediated nitric oxide release in PA endothelial cells, and promotes endothelium-independent vasodilation while attenuating pulmonary vascular remodeling via inhibition of NAD(P)H oxidase-reactive oxygen species signaling and activation of the Nrf2/superoxide dismutase signaling. Restoring reduced salusin-α may present a novel therapeutic strategy for PH treatment.