Suppression of Phosphatidylinositol 3-Kinase/Akt Signaling Attenuates Hypoxia-Induced Pulmonary Hypertension Through the Downregulation of Lysyl Oxidase
| Autor: | Sajid Khan, Xiao-Dong Xia, Le-Ping Ye, Liang Dong, Jasmine Lee, Yuan Li |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Hypertension Pulmonary Gene Expression Lysyl oxidase Biology Wortmannin Protein-Lysine 6-Oxidase Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Genetics medicine Animals Phosphatidylinositol Hypoxia Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Cell Biology General Medicine Hypoxia (medical) Molecular biology Specific Pathogen-Free Organisms 030104 developmental biology chemistry 030220 oncology & carcinogenesis Aminopropionitrile medicine.symptom Signal transduction Signal Transduction |
| Zdroj: | DNA and cell biology. 35(10) |
| ISSN: | 1557-7430 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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