ROCK Pathway Participates in the Processes That 15-Hydroxyeicosatetraenoic Acid (15-HETE) Mediated the Pulmonary Vascular Remodeling Induced by Hypoxia in Rat

15-Hydroxyeicosatetraenoic acid (15-HETE), a product of arachidonic acid (AA) catalyzed by 15-lipoxygenase (15-LO), plays an essential role in hypoxic pulmonary arterial hypertension. We have previously shown that 15-HETE inhibits apoptosis in pulmonary artery smooth muscle cells (PASMCs). To test the hypothesis that such an effect is attributable to the hypoxia-induced pulmonary vascular remodeling (PVR), we performed these studies. We found subtle thickening of proximal media/adventitia of the pulmonary arteries (PA) in rats that had been exposed to hypoxia. This was associated with an up-regulation of the anti-apoptotic Bcl-2 expression and down-regulation of pro-apoptotic caspase-3 and Bax expression in PA homogenates. Nordihydroguaiaretic acid (NDGA), which inhibits the generation of endogenous 15-HETE, reversed all the alterations following hypoxia. In situ hybridization histochemistry and immunocytochemistry showed that the 15-LO-1 mRNA and protein were localized in pulmonary artery endothelial cells (PAECs), while the 15-LO-2 mRNA and protein were localized in both PAECs and PASMCs. Furthermore, the Rho-kinase (ROCK) pathway was activated by both endogenous and exogenous 15-HETE, alleviating the serum deprivation (SD)-induced PASMC apoptosis. Thus, these findings indicate that 15-HETE protects PASMC from apoptosis, contributing to pulmonary vascular medial thickening, and the effect is, at least in part, mediated via the ROCK pathway. J. Cell. Physiol. 222: 82-94, 2010. (C) 2009 Wiley-Liss, Inc.