Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 229, Issue 2, Pages 245-257Publisher
WILEY-BLACKWELL
DOI: 10.1002/jcp.24443
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Funding
- Heilongjiang Postdoctoral Fund [LBH-Z12203]
- Educational Bureau [12531297]
- Department of Health of Heilongjiang Province [2012-779]
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15-Lipoxygenase/15-hydroxyeicosatetraenoic acid (15-LO/15-HETE) is known to modulate pulmonary vascular medial hypertrophy and intimal endothelial cells migration and angiogenesis after hypoxia. However, it is unclear whether 15-HETE affects the adventitia of the pulmonary arterial wall. We performed immunohistochemistry, adventitia fibrosis, pulmonary artery fibroblasts phenotype and extracellular matrix (ECM) deposition to determine the role of 15-HETE in hypoxia-induced pulmonary vascular adventitia remodeling. Our studies showed that O-2 deprivation induced adventitia hypertrophy of pulmonary arteries with ECM accumulation in both humans with pulmonary arterial hypertension and hypoxic rats. Hypoxia induced 15-LO expression in adventitia. With the inhibitor, NDGA depressed the hypoxia induced ECM deposition and 15-LO production in hypoxic rats. Hypoxia up-regulated the expression of -SMA, type-Ia collagen and fibronectin in cultured fibroblasts, which seemed to be due to the increased 15-LO/15-HETE. Exogenous 15-HETE mediated the ECM and phenotypic alterations of the fibroblasts as well. The 15-LO/15-HETE induced adventitia fibrosis and fibroblasts phenotypic alterations depended on signaling of the transforming growth factor-1 (TGF-1)/Smad2/3 pathway. P38 mitogen-activated protein kinase (p38 MAPKs) was likely to mediate 15-LO induced TGF-1 and Smad2/3 activation after hypoxia. The results suggest that adventitia fibrosis is an important event in the hypoxia induced pulmonary arterial remodeling, which relies on 15-LO/15-HETE induced p38 MAPK-dependent TGF-1/Smad2/3 intracellular signaling systems. J. Cell. Physiol. 229: 245-257, 2014. (c) 2013 Wiley Periodicals, Inc.
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