title: Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction.
abstract: Emerging evidence is revealing the different roles of steady laminar flow (s-flow) and disturbed flow (d-flow) in the regulation of the vascular endothelium. s-flow is atheroprotective while d-flow creates an atheroprone environment. Most recently, we found unique atheroprone signals, which involve protein kinase C (PKC)ζ activation, elicited by d-flow. We and others have defined a novel role for PKCζ as a shared mediator for tumor necrosis factor alpha (TNF alpha) and d-flow, which cause pro-inflammatory and pro-apoptotic events in endothelial cells (ECs) in the atheroprone environment. Under such conditions, ONOO(-) formation is increased in a d-flow-mediated PKCζ-dependent manner. Here, we propose a new signaling pathway involving d-flow-induced EC inflammation via PKCζ-ERK5 interaction-mediated downregulation of KLF2/eNOS stability, which leads to PKCζ-mediated p53-SUMOylation and EC apoptosis. In addition, we highlight several mechanisms contributing to endothelial dysfunction, focusing on the relations between flow patterns and activation of reactive oxygen species generating enzymes.
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester, NY, USA.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Heo
authors.forename: Keigi
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Abe
mesh_terms: D017209:Apoptosis; D050197:Atherosclerosis / Q000097:blood* / Q000473:pathology / Q000503:physiopathology; D001783:Blood Flow Velocity; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D007527:Isoenzymes / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D017382:Reactive Oxygen Species / Q000097:blood*; D015398:Signal Transduction; D058207:Sumoylation; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D007527:Isoenzymes; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D048054:Mitogen-Activated Protein Kinase 7
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