Heme oxygenase-1 induces 15-lipoxygenase expression during hypoxia-induced pulmonary hypertension

We previously reported that 15-lipoxygenase (15-LO) induced by hypoxia catalyzed the conversion of arachidonic acid (AA) into 15-hydroxyeicosatetraenoic acid (15-HETE), which plays an essential role in the development of hypoxic pulmonary arterial hypertension (HPH). However, the mechanisms by which hypoxia up-regulated 15-LO are still unclear. Heme oxygenase-1 (HO-1), an oxygen-dependent enzyme regulating vascular tone and cell proliferation, was implicated in HPH and was promoted by hypoxia. Therefore, the present study was carried out to determine whether hypoxia induced the expression of 15-LO via the HO-1 pathway. To test this hypothesis, we studied the role of HO-1 in HPH and 15-LO/15-HETE expression We found increased right ventricular systolic pressure and pulmonary arteries (PAs) reactivity to vasoconstrictors as well as intima-to-media ratio of PAs in HO-1 overexpressing transgenic mice. Moreover, HO-1 up-regulated 15-LO transcription and translation as well as 15-HETE in both transgenic mice and cultured pulmonary arterial smooth muscle cells (PASMCs). Results from immunoprecipitation and immunocytochemistry showed the interaction and colocalization of HO-1 and 15-LO. Together, these data suggest that HO-1 is an important upstream mediator in the hypoxia-induced 15-LO up-regulation during HPH. Unveiling the relevance of HO-1 signaling in PHP provides attractive treatment targets for HPH.