title: Reciprocal regulation of HIF-1α and 15-LO/15-HETE promotes anti-apoptosis process in pulmonary artery smooth muscle cells during hypoxia.
abstract: 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-1α (HIF-1α) 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-1α and 15-LO/15-HETE in hypoxic pulmonary artery smooth muscle cells. Our results showed that HIF-1α inhibitor or siRNA reduced hypoxia-induced upregulation of 15-LO and endogenous 15-HETE, meanwhile HIF-1α 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-1α 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-1α 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-1α which is also regulated by 15-HETE in a positive feedback manner, and HIF-1α can effectively inhibit pulmonary artery smooth muscle cells apoptosis which leads to vascular remodeling. The feedback loop between HIF-1α and 15-LO/15-HETE would obviously reinforce hypoxia-induced anti-apoptosis effect and may become a novel target of therapy in PAH.
authors.affiliation: Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yao
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Nie
authors.forename: Shuai
authors.initials: S
authors.lastname: Shi
authors.forename: Shasha
authors.initials: S
authors.lastname: Song
authors.forename: Xuewei
authors.initials: X
authors.lastname: Hao
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Li
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C497444:Hif1a protein, rat; D006893:Hydroxyeicosatetraenoic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D034741:RNA, Small Interfering; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001093:Arachidonate 15-Lipoxygenase