Apple polyphenol relieves hypoxia-induced pulmonary arterial hypertension via pulmonary endothelium protection and smooth muscle relaxation: In vivo and in vitro studies.

Graphical abstract Highlights • Apple polyphenol relieves mean pulmonary arterial pressure, pulmonary vessel resistance in hypoxia-induced pulmonary hypertension model of rat. • After apple polyphenol administration, both endothelium intact and removed pulmonary vessel rings constricted by KCl or phenylephrine are relaxed. • Apple polyphenol up-regulates Ca2+ efflux and K+ influx in pulmonary arterial smooth muscle cell. • Apple polyphenol reduces pulmonary artery endothelium cell injury and apoptosis under hypoxia, and up-regulates NO level by enhancing endothelial nitric oxide synthase. Abstract Aim This study aims to test the effect of apple polyphenol (APP) on hypoxia-induced pulmonary arterial hypertension (PAH) and explore its possible underlying mechanisms. Methods and results Rats were treated with control, APP, hypoxia (8 h/d), hypoxia + APP. Mean pulmonary arterial pressure (mPAP) and pulmonary vessel resistance (PVR) were examined. Phenylephrine (PE)-pretreated pulmonary vessel rings were prepared for observation of APP administration. eNOS, sGC inhibitors (L-NAME, MB), Ca2+ channel blockers (NiCl 2 , Calhex231), K+ channel blockers (4-AP, 5-HD, TEA, BaCl 2) were applied to pulmonary vessel rings and pulmonary arterial smooth muscle cell (PASMC). Flow cytometry analysis and CCK-8 assay were applied to detect apoptosis of pulmonary artery endothelium cell (PAEC). Caspase-3, NO, eNOS, iNOS were detected in PAEC. APP reversed mPAP and PVR elevation in vivo. Contraction of pulmonary vessel rings with/without endothelium induced by hypoxia were inhibited by APP. APP effect was hindered by L-NAME or MB, and could be reduced by K+channel blockers. Further, APP was found to decrease cytosolic Ca2+ in PASMC and protect PAEC from apoptosis. In PAEC, Caspase-3, iNOS were decreased and NO, eNOS were increased after APP administration. Conclusions APP reverses pulmonary vasoconstriction through enzyme expression and cation channel activities, thus has effects of PASMC relaxation and PAEC protection. [ABSTRACT FROM AUTHOR]