title: Activation of JNK/c-Jun is required for the proliferation, survival, and angiogenesis induced by EET in pulmonary artery endothelial cells.
abstract: Pulmonary artery endothelial plexiform lesion is responsible for pulmonary vascular remodeling (PVR), a basic pathological change of pulmonary arterial hypertension (PAH). Recent evidence suggests that epoxyeicosatrienoic acid (EET), which is derived from arachidonic acid by cytochrome p450 (CYP) epoxygenase, has an essential role in PAH. However, until now, most research has focused on pulmonary vasoconstriction; it is unclear whether EET produces mitogenic and angiogenic effects in pulmonary artery endothelial cells (PAEC). Here we found that 500 nM/l 8,9-EET, 11,12-EET, and 14,15-EET markedly augmented JNK and c-Jun activation in PAECs and that the activation of c-Jun was mediated by JNK, but not the ERK or p38 MPAK pathway. Moreover, treatment with 8,9-EET, 11,12-EET, and 14,15-EET promoted cell proliferation and cell-cycle transition from the G0/G1 phase to S phase and stimulated tube formation in vitro. All these effects were reversed after blocking JNK with Sp600125 (a JNK inhibitor) or JNK1/2 siRNA. In addition, the apoptotic process was alleviated by three EET region isomers through the JNK/c-Jun pathway. These observations suggest that 8,9-EET, 11,12-EET, and 14,15-EET stimulate PAEC proliferation and angiogenesis, as well as protect the cells from apoptosis, via the JNK/c-Jun pathway, an important underlying mechanism that may promote PAEC growth and angiogenesis during PAH.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University Daqing, Daqing 163319, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Weina
authors.initials: W
authors.lastname: Han
authors.forename: Tingting
authors.initials: T
authors.lastname: Shen
authors.forename: Cui
authors.initials: C
authors.lastname: Ma
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Nie
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Liu
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Ran
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D020868:Gene Silencing; D007399:Interphase / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010750:Phosphoproteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology*; D015398:Signal Transduction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; D048031:JNK Mitogen-Activated Protein Kinases; D015126:8,11,14-Eicosatrienoic Acid