title: Flow-dependent expression of ectonucleotide tri(di)phosphohydrolase-1 and suppression of atherosclerosis.
abstract: The ability of cells to detect and respond to nucleotide signals in the local microenvironment is essential for vascular homeostasis. The enzyme ectonucleotide tri(di)phosphohydrolase-1 (ENTPD1, also known as CD39) on the surface of leukocytes and endothelial cells metabolizes locally released, intravascular ATP and ADP, thereby eliminating these prothrombotic and proinflammatory stimuli. Here, we evaluated the contribution of CD39 to atherogenesis in the apolipoprotein E-deficient (ApoE-deficient) mouse model of atherosclerosis. Compared with control ApoE-deficient animals, plaque burden was markedly increased along with circulating markers of platelet activation in Cd39+/-Apoe-/- mice fed a high-fat diet. Plaque analysis revealed stark regionalization of endothelial CD39 expression and function in Apoe-/- mice, with CD39 prominently expressed in atheroprotective, stable flow regions and diminished in atheroprone areas subject to disturbed flow. In mice, disturbed flow as the result of partial carotid artery ligation rapidly suppressed endothelial CD39 expression. Moreover, unidirectional laminar shear stress induced atheroprotective CD39 expression in human endothelial cells. CD39 induction was dependent upon the vascular transcription factor Krüppel-like factor 2 (KLF2) binding near the transcriptional start site of CD39. Together, these data establish CD39 as a regionalized regulator of atherogenesis that is driven by shear stress.
authors.forename: Yogendra
authors.initials: Y
authors.lastname: Kanthi
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Hyman
authors.forename: Hui
authors.initials: H
authors.lastname: Liao
authors.forename: Amy E
authors.initials: AE
authors.lastname: Baek
authors.forename: Scott H
authors.initials: SH
authors.lastname: Visovatti
authors.forename: Nadia R
authors.initials: NR
authors.lastname: Sutton
authors.forename: Sascha N
authors.initials: SN
authors.lastname: Goonewardena
authors.forename: Mithun K
authors.initials: MK
authors.lastname: Neral
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D000244:Adenosine Diphosphate / Q000097:blood; D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics; D001081:Apyrase / Q000096:biosynthesis* / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001783:Blood Flow Velocity / Q000187:drug effects / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics; D020218:Response Elements; D033081:Shear Strength
chemical_list: D015703:Antigens, CD; D001057:Apolipoproteins E; D004041:Dietary Fats; C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen