title: Disturbed Flow-Induced Endothelial Proatherogenic Signaling Via Regulating Post-Translational Modifications and Epigenetic Events.
abstract: Hemodynamic shear stress, the frictional force exerted onto the vascular endothelial cell (EC) surface, influences vascular EC functions. Atherosclerotic plaque formation in the endothelium is known to be site specific: disturbed blood flow (d-flow) formed at the lesser curvature of the aortic arch and branch points promotes plaque formation, and steady laminar flow (s-flow) at the greater curvature is atheroprotective.
  
  
  
  Post-translational modifications (PTMs), including phosphorylation and SUMOylation, and epigenetic events, including DNA methylation and histone modifications, provide a new perspective on the pathogenesis of atherosclerosis, elucidating how gene expression is altered by d-flow. Activation of PKCζ and p90RSK, SUMOylation of ERK5 and p53, and DNA hypermethylation are uniquely induced by d-flow, but not by s-flow.
  
  
  
  Extensive cross talk has been observed among the phosphorylation, SUMOylation, acetylation, and methylation PTMs, as well as among epigenetic events along the cascade of d-flow-induced signaling, from the top (mechanosensory systems) to the bottom (epigenetic events). In addition, PKCζ activation plays a role in regulating SUMOylation-related enzymes of PIAS4, p90RSK activation plays a role in regulating SUMOylation-related enzymes of Sentrin/SUMO-specific protease (SENP)2, and DNA methyltransferase SUMOylation may play a role in d-flow signaling.
  
  
  
  Although possible contributions of DNA events such as histone modification and the epigenetic and cytosolic events of PTMs in d-flow signaling have become clearer, determining the interplay of each PTM and epigenetic event will provide a new paradigm to elucidate the difference between d-flow and s-flow and lead to novel therapeutic interventions to inhibit plaque formation. Antioxid. Redox Signal. 25, 435-450.
authors.affiliation: 1 Department of Cardiology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center , Houston, Texas.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Heo
authors.affiliation: 2 Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester Medical Center , Rochester, New York.
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
authors.affiliation: 1 Department of Cardiology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center , Houston, Texas.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Abe
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers; D019175:DNA Methylation; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012039:Regional Blood Flow; D015398:Signal Transduction; D058207:Sumoylation
chemical_list: D015415:Biomarkers; D058847:Inflammasomes