15-PGDH/15-KETE plays a role in hypoxia-induced pulmonary vascular remodeling through ERK1/2-dependent PAR-2 pathway

• Published in: Cellular signalling 2014-07, Vol.26 (7), p.1476-1488
• Main Authors: Wei, Liuping, Yu, Xiufeng, Shi, Hengyuan, Zhang, Bo, Lian, Mingming, Li, Jing, Shen, Tingting, Xing, Yan, Zhu, Daling
• Format: Article
• Language: English
• Subjects: 15-Ketoeicosatetraenoic acid; Animals; Arachidonic Acids - chemistry; Arachidonic Acids - metabolism; Cell Cycle; Cell Cycle Proteins - biosynthesis; Cell Hypoxia; Cell Proliferation; Cells, Cultured; Control; Eicosapentaenoic Acid - analogs & derivatives; Eicosapentaenoic Acid - chemistry; Eicosapentaenoic Acid - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Humans; Hydroxyprostaglandin Dehydrogenases - genetics; Hydroxyprostaglandin Dehydrogenases - metabolism; Hypertension; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - metabolism; Hypoxia; Lung - blood supply; Lung - pathology; Male; MAP Kinase Signaling System; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Muscles; Myocytes, Smooth Muscle - metabolism; Pathways; Progressions; Proliferation; Protease-activated receptor-2; Pulmonary arterial smooth muscle cell; Pulmonary Artery - cytology; Pulmonary vascular remodeling; Random Allocation; Rats; Rats, Wistar; Receptor, PAR-2 - biosynthesis; Receptor, PAR-2 - genetics; Receptor, PAR-2 - metabolism; Remodeling; RNA Interference; RNA, Small Interfering; Vascular Remodeling - genetics
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2014.03.008

We have established that 15-hydroxyeicosatetraenoic acid is an important factor in regulation of pulmonary vascular remodeling (PVR) associated with hypoxia-induced pulmonary hypertension (PH), which is further metabolized by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) to form 15-ketoeicosatetraenoic acid (15-KETE). However, the role of 15-PGDH and 15-KETE on PH has not been identified. The purpose of this study was to investigate whether 15-PGDH/15-KETE pathway regulates hypoxia-induced PVR in PH and to characterize the underlying mechanisms. To accomplish this, Immunohistochemistry, Ultra Performance Liquid Chromatography, Western blot, bromodeoxyuridine incorporation and cell cycle analysis were preformed. Our results showed that the levels of 15-PGDH expression and endogenous 15-KETE were drastically elevated in the lungs of humans with PH and hypoxic PH rats. Hypoxia stimulated pulmonary arterial smooth muscle cell (PASMC) proliferation, which seemed to be due to the increased 15-PGDH/15-KETE. 15-PGDH/15-KETE pathway was also capable of stimulating the cell cycle progression and promoting the cell cycle-related protein expression. Furthermore, 15-KETE-promoted cell cycle progression and proliferation in PASMCs depended on protease-activated receptor 2 (PAR-2). ERK1/2 signaling was likely required for 15-PGDH/15-KETE-induced PAR-2 expression under hypoxia. Our study indicates that 15-PGDH/15-KETE stimulates the cell cycle progression and proliferation of PASMCs involving ERK1/2-mediated PAR-2 expression, and contributes to hypoxia-induced PVR. •15-PGDH/15-KETE pathway is induced in PH.•Hypoxia promotes PASMC proliferation via 15-PGDH/15-KETE pathway.•15-PGDH/15-KETE pathway stimulates PASMC proliferation through PAR-2.•15-PGDH/15-KETE pathway up-regulates PAR-2 via ERK1/2 to promote PASMC proliferation.