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.
Ma
Jun
J
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Nangang District, Harbin, Heilongjiang, PR China.
Liang
Shujun
S
Wang
Zhigang
Z
Zhang
Lei
L
Jiang
Jing
J
Zheng
Jinhua
J
Yu
Lei
L
Zheng
Xiaodong
X
Wang
Ruifang
R
Zhu
Daling
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009637:Masoprocol / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D006893:Hydroxyeicosatetraenoic Acids; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D009637:Masoprocol; D001093:Arachidonate 15-Lipoxygenase; D054460:rho-Associated Kinases; D053148:Caspase 3