title: Transglutaminase activity regulates atherosclerotic plaque composition at locations exposed to oscillatory shear stress.
abstract: OBJECTIVE
  Atherosclerosis preferentially develops at sites of disturbed blood flow. We tested the hypothesis that transglutaminase activity plays a role in plaque development at these locations.
  
  
  RESULTS
  Exposure of endothelial cells to steady flow (7 dynes/cm(2)) was associated with relatively low transglutaminase activity, whereas under low oscillatory flow (1.3 ± 2.6 dynes/cm(2)) endothelial cells showed a >4-fold higher level of transglutaminase activity. Under oscillatory flow, transglutaminase activity increased the expression of the chemokine MCP-1 (CCL2). In vivo, oscillatory flow was induced by placement of a tapered perivascular cast around the carotid artery of type 2 transglutaminase (TGM2) knockout mice and WT counterparts. After 2 days, significantly less monocytes adhered to the endothelium in TGM2 knockout mice as compared to WT. In a more chronic setting, ApoE knockout mice that were equipped with the flow-modifying cast developed lesions proximal to the cast (low shear stress), and distal to the cast (oscillatory shear stress). Inhibition of transglutaminase induced a marked reduction in macrophage and fat content in distal lesions only. In addition, lesion size was increased in this area, which was attributed to an increase in smooth muscle content.
  
  
  CONCLUSIONS
  Oscillatory shear stress increases endothelial transglutaminase activity. In turn, transglutaminase activity affects the expression of MCP-1 in vitro and monocyte recruitment in vivo. In a mouse model of atherosclerosis, transglutaminase activity has a major effect on plaque composition under oscillatory shear stress.
authors.affiliation: Department of Biomedical Engineering and Physics, Academic Medical Center, PO Box 22700, 1100 DE Amsterdam, The Netherlands.
authors.forename: Hanke L
authors.initials: HL
authors.lastname: Matlung
authors.forename: Annette E
authors.initials: AE
authors.lastname: Neele
authors.forename: Harald C
authors.initials: HC
authors.lastname: Groen
authors.forename: Kim
authors.initials: K
authors.lastname: van Gaalen
authors.forename: Bilge Guvenc
authors.initials: BG
authors.lastname: Tuna
authors.forename: Angela
authors.initials: A
authors.lastname: van Weert
authors.forename: Judith
authors.initials: J
authors.lastname: de Vos
authors.forename: Jolanda J
authors.initials: JJ
authors.lastname: Wentzel
authors.forename: Mark
authors.initials: M
authors.lastname: Hoogenboezem
authors.forename: Jaap D
authors.initials: JD
authors.lastname: van Buul
authors.forename: Ed
authors.initials: E
authors.lastname: VanBavel
authors.forename: Erik N T P
authors.initials: EN
authors.lastname: Bakker
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D002448:Cell Adhesion; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D058226:Plaque, Atherosclerotic; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013997:Time Factors; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001057:Apolipoproteins E; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; C000717608:TGM2 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins