title: Protective effect of nicorandil on hypoxia‑induced apoptosis in HPAECs             through inhibition of p38 MAPK phosphorylation.
abstract: Endothelial cell apoptosis is induced under various conditions, including             hypoxia, which is crucial for pulmonary hypertension. The present study aimed             to investigate the protective effect of nicorandil against hypoxia‑induced apoptosis             in human pulmonary arterial endothelial cells (HPAEC) and the potential mechanisms             involved in the regulation of p38 mitogen‑activated protein kinase (MAPK). Following             exposure to hypoxia for 24 h, 3‑(4,5‑dimethylthiazol‑2yl‑)‑2,5‑diphenyltetrazolium             bromide assay was performed to measure cell viability. Annexin V‑propidium iodide             double staining with ﬂow cytometry and fluorescence staining of cells with Hoechst 33342             was then used to detect apoptosis. Expression of phosphorylated (phospho)‑p38             MAPK, Bcl‑2‑associated X protein, B‑cell lymphoma 2, caspase‑8, ‑9 and ‑3 and             endothelial nitric oxide synthase (eNOS) was assayed by western blotting to investigate             the mechanisms of action. Results showed that hypoxia significantly decreases             cell viability by inducing cell apoptosis, while nicorandil and the p38 MAPK inhibitor,             SB203580, reversed hypoxia‑induced apoptosis. Nicorandil and SB203580 consistently             inhibited the phosphorylation of p38 MAPK and expression of various apoptosis‑related             proteins induced by hypoxia. However, nicorandil increased the hypoxia‑induced             downregulation of eNOS expression and the effects of nicorandil were completely             blocked by the mitochondrial ATP‑sensitive potassium (mitoKATP) channel antagonist,             5‑hydroxydecanoate. Nicorandil was identified to protect HPAEC from hypoxia‑induced             apoptosis by activating mitoKATP channels. The mechanisms by which this protective             effect is mediated may involve inhibition of phospho‑p38 MAPK and downstream cell             death pathways.
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: Yanzhe
authors.initials: Y
authors.lastname: Yu
authors.forename: Yonglong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Junyang
authors.initials: J
authors.lastname: Li
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Zuo
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Weiping
authors.initials: W
authors.lastname: Xie
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020108:Nicorandil / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D011725:Pyridines; D014665:Vasodilator Agents; D051028:bcl-2-Associated X Protein; D020108:Nicorandil; D052250:Nitric Oxide Synthase Type III; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C093642:SB 203580