期刊
PROSTAGLANDINS & OTHER LIPID MEDIATORS
卷 99, 期 3-4, 页码 96-106出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.prostaglandins.2012.09.001
关键词
HIF-1 alpha; 15-HETE; 15-LO; Feedback; Apoptosis
15-Hydroxyeicosatetraenoic acid, a predominant metabolic product of arachidonic acid (AA) catalyzed by 15-lipoxygenase (15-LO), plays an important role in hypoxic pulmonary arterial hypertension (PAH). Hypoxia-inducible factor-1 alpha (HIF-1 alpha) as a critical oxygen-sensitive transcriptional factor participates in many physiological and pathological processes including PAH. Therefore, it is possible that there may be some connections between HIF-1 alpha and 15-LO/15-HETE in hypoxic pulmonary artery smooth muscle cells. Our results showed that HIF-1 alpha inhibitor or siRNA reduced hypoxia-induced upregulation of 15-LO and endogenous 15-HETE, meanwhile HIF-1 alpha expression and transcriptional activity were induced by 15-HETE under both normoxic and hypoxic conditions. It suggests there exists a potential positive feedback regulatory loop between HIF-1 alpha and 15-LO/15-HETE. Furthermore, cell viability assay and several cell apoptosis assays, including TUNEL assay, Western blot, nuclear morphology determination, mitochondrial potential analysis, indicated that blocking HIF-1 alpha induced apoptosis, decreased cell viability and suppressed the anti-apoptosis effects of 15-HETE. Taken together, our data indicate that upregulation of 15-LO/15-HETE in response to hypoxia may be partially mediated by HIF-1 alpha which is also regulated by 15-HETE in a positive feedback manner, and HIF-1 alpha can effectively inhibit pulmonary artery smooth muscle cells apoptosis which leads to vascular remodeling. The feedback loop between HIF-1 alpha and 15-LO/15-HETE would obviously reinforce hypoxia-induced anti-apoptosis effect and may become a novel target of therapy in PAH. (c) 2012 Elsevier Inc. All rights reserved.
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