Cigarette smoke extract induces HO-1 expression in mouse cerebral vascular endothelial cells: involvement of c-Src/NADPH oxidase/PDGFR/JAK2/STAT3 pathway.
Several chemicals present in cigarette smoke (CS) have been reported to induce heme oxygenase-1 (HO-1) expression, which represents a prime defense mechanism in protecting the cells from stress-dependent adverse effects on peripheral vascular system. However, the effects of cigarette smoke extract (CSE) on HO-1 induction and the mechanisms underlying CSE-induced HO-1 expression in brain vessels are not completely understood. Here, we used a mouse brain endothelial cell culture (bEnd.3) to investigate the effect of CSE on HO-1 induction and the mechanisms underlying CSE-induced HO-1 expression in cerebral vessels. We demonstrated that sublethal concentrations of CSE (30 µg/ml) induced submaximal HO-1 expression in bEnd.3 cells. NADPH oxidase-dependent ROS generation played a key role in CSE-induced HO-1 expression. CSE-induced HO-1 expression was mediated through PDGFR/JAK2/STAT3 cascade, which was observed by pretreatment with the respective pharmacological inhibitors or transfection with PDGFR shRNA. CSE activated NADPH oxidase through c-Src in bEnd.3 cells. Taken together, these results suggested that, in bEnd.3 cells, CSE-induced HO-1 expression was mediated through PDGFR/JAK2/STAT3 cascade, which was regulated by c-Src or c-Src activated-NADPH oxidase/ROS.
Shih
Ruey-Horng
RH
Department of Physiology and Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.
Lee
I-Ta
IT
Hsieh
Hsi-Lung
HL
Kou
Yu Ru
YR
Yang
Chuen-Mao
CM
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000098:blood supply*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D053614:Janus Kinase 2 / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008565:Membrane Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D012906:Smoke; C494087:Stat3 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019255:NADPH Oxidases; D017479:Receptors, Platelet-Derived Growth Factor; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D019061:src-Family Kinases