Reciprocal regulation of HIF-1α and 15-LO/15-HETE promotes anti-apoptosis process in pulmonary artery smooth muscle cells during hypoxia

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.

► 15-LO is a target gene of HIF-1α. ► 15-HETE induces HIF-1α expression via a feedback regulation mechanism. ► 15-HETE increases HIF-1α transcriptional activity. ► There was no protein–protein interaction between 15-LO and HIF-1α. ► HIF-1α/15-HETE pathway effectively inhibits PASMC apoptosis.