title: Bone morphogenic protein-4 induces endothelial cell apoptosis through oxidative stress-dependent p38MAPK and JNK pathway.
abstract: The expression of bone morphogenic protein 4 (BMP4), a new pro-inflammatory marker, is increased by disturbed flow in endothelial cells (ECs). BMP4 stimulates production of reactive oxygen species (ROS) and causes endothelial cell dysfunction. The present study examined BMP4-induced apoptosis in ECs and isolated arteries from rat, mouse, and human, and the signaling pathways mediating BMP4-induced apoptosis. Apoptosis was assessed by flow cytometry to detect Annexin-V positive cells, and terminal deoxynucleotidyl transferase dUTP nick end (TUNEL) labeling. The superoxide production was measured by dihydroethidium fluorescence. BMP4 induced EC apoptosis in human mesenteric arteries, mouse aortic endothelium, rat primary ECs, and human ECs. BMP4-induced EC apoptosis was mediated through ROS production by activation of NADPH oxidase, which led to cleaved caspase-3 expression. BMP4 also induced sequential activation of p38 MAPK and JNK which was upstream of caspase 3 activation. Knockdown of BMP receptor 1A by lentiviral shRNA or NOX4 siRNA transfection inhibited BMP4-induced ROS production, p38 and JNK phosphorylation, and caspase-3 activation in ECs. JNK siRNA inhibited BMP4-induced JNK phosphorylation and caspase-3 activation. The present study delineates that BMP4 causes EC apoptosis through activation of caspase-3 in a ROS/p38MAPK/JNK-dependent signaling cascade.
authors: Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong SAR, China.
authors: Xiao Yu
authors: XY
authors: Tian
authors: Lai Hang
authors: LH
authors: Yung
authors: Wing Tak
authors: WT
authors: Wong
authors: Jian
authors: J
authors: Liu
authors: Fung Ping
authors: FP
authors: Leung
authors: Limei
authors: L
authors: Liu
authors: Yangchao
authors: Y
authors: Chen
authors: Siu Kai
authors: SK
authors: Kong
authors: Kin Ming
authors: KM
authors: Kwan
authors: Siu Man
authors: SM
authors: Ng
authors: Paul B S
authors: PB
authors: Lai
authors: Lai Ming
authors: LM
authors: Yung
authors: Xiaoqiang
authors: X
authors: Yao
authors: Yu
authors: Y
authors: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D055415:Bone Morphogenetic Protein 4; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I; D053148:Caspase 3