title: Suppression of Phosphatidylinositol 3-Kinase/Akt Signaling Attenuates Hypoxia-Induced Pulmonary Hypertension Through the Downregulation of Lysyl Oxidase.
abstract: Lysyl oxidase (LOX) is a copper-dependent enzyme that catalyzes covalent cross-linking of collagen. In response to hypoxia, phosphatidylinositol 3-kinase (PI3K) pathway is activated and contributes to pulmonary arterial hypertension (PAH). However, potential role of LOX in hypoxia-induced PAH is poorly understood. In this study, we explored the mechanism responsible for the development of hypoxia-induced PAH. Potent inhibitors of PI3K/Akt and LOX, wortmannin and β-aminopropionitrile (β-APN), were administrated in rat model of hypoxia-induced PAH. The cross-linking of collagen was assessed by the determination of hydroxyproline. LOX, LOXL-1, LOXL-2, LOXL-3, LOXL-4, Akt, and phospho-Akt expression was detected by real-time polymerase chain reaction and western blot analysis. We observed that collagen cross-linking and LOX activity were elevated in hypoxia-exposed rat lung tissue, but these effects were reversed by β-APN and wortmannin. In addition, exposure to hypoxia enhanced mRNA and protein expression and activity of LOX and LOXL-1 in a PI3K/Akt-dependent manner and induced the development of PAH. After the administration of wortmannin, the upregulation of LOX and cross-linking of collagen were significantly reversed in hypoxia-exposed rat pulmonary artery tissue. Taken together, the present study demonstrated that the upregulation of LOX expression and collagen cross-linking is PI3K/Akt dependent in rat with hypoxia-induced PAH. Suppression of PI3K/Akt pathway may alleviate hypoxia-induced PAH through the downregulation of LOX.
authors.affiliation: 1 Department of Respiratory Medicine, Qilu Hospital of Shandong University , Jinan, China .|2 Department of Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou, China .
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Xia
authors.affiliation: 3 Department of Respiratory Medicine, Royal Free and Barnet Hospital , London NHS Foundation Trust, London, United Kingdom .
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lee
authors.affiliation: 3 Department of Respiratory Medicine, Royal Free and Barnet Hospital , London NHS Foundation Trust, London, United Kingdom .
authors.forename: Sajid
authors.initials: S
authors.lastname: Khan
authors.affiliation: 2 Department of Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou, China .
authors.forename: Leping
authors.initials: L
authors.lastname: Ye
authors.affiliation: 2 Department of Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou, China .
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1 Department of Respiratory Medicine, Qilu Hospital of Shandong University , Jinan, China .
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
mesh_terms: D000629:Aminopropionitrile / Q000008:administration & dosage; D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000235:genetics; D000860:Hypoxia / Q000150:complications*; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013047:Specific Pathogen-Free Organisms
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D000629:Aminopropionitrile; D008249:Protein-Lysine 6-Oxidase
keywords: hypoxia; lysyl oxidase; phosphatidylinositol 3-kinase; pulmonary hypertension