title: Endothelial PPAR-γ protects against vascular thrombosis by downregulating P-selectin expression.
abstract: OBJECTIVE
  We tested the hypothesis that endothelial peroxisome proliferator-activated receptor-γ protects against vascular thrombosis using a transgenic mouse model expressing a peroxisome proliferator-activated receptor-γ mutant (E-V290M) selectively in endothelium.
  
  
  RESULTS
  The time to occlusive thrombosis of the carotid artery was significantly shortened in E-V290M mice compared with nontransgenic littermates after either chemical injury with ferric chloride (5.1 ± 0.2 versus 10.1 ± 3.3 minutes; P=0.01) or photochemical injury with rose bengal (48 ± 9 versus 74 ± 9 minutes; P=0.04). Gene set enrichment analysis demonstrated the upregulation of NF-κB target genes, including P-selectin, in aortic endothelial cells from E-V290M mice (P<0.001). Plasma P-selectin and carotid artery P-selectin mRNA were elevated in E-V290M mice (P<0.05). P-selectin-dependent leukocyte rolling on mesenteric venules was increased in E-V290M mice compared with nontransgenic mice (53 ± 8 versus 25 ± 7 per minute; P=0.02). The shortened time to arterial occlusion in E-V290M mice was reversed by administration of P-selectin-blocking antibodies or neutrophil-depleting antibodies (P=0.04 and P=0.02, respectively) before photochemical injury.
  
  
  CONCLUSIONS
  Endothelial peroxisome proliferator-activated receptor-γ protects against thrombosis through a mechanism that involves downregulation of P-selectin expression and diminished P-selectin-mediated leukocyte-endothelial interactions.
authors: From the Departments of Internal Medicine (H.J., M.A.G., I.O.B., K.M.W., A.K.C., C.D.S., S.R.L.) and Pharmacology (P.K., H.L.K., C.D.S.), Interdisciplinary Graduate Program in Molecular and Cellular Biology (I.O.B.), University of Iowa Carver College of Medicine, Iowa City.
authors: Hong
authors: H
authors: Jin
authors: From the Departments of Internal Medicine (H.J., M.A.G., I.O.B., K.M.W., A.K.C., C.D.S., S.R.L.) and Pharmacology (P.K., H.L.K., C.D.S.), Interdisciplinary Graduate Program in Molecular and Cellular Biology (I.O.B.), University of Iowa Carver College of Medicine, Iowa City.
authors: Milena A
authors: MA
authors: Gebska
authors: From the Departments of Internal Medicine (H.J., M.A.G., I.O.B., K.M.W., A.K.C., C.D.S., S.R.L.) and Pharmacology (P.K., H.L.K., C.D.S.), Interdisciplinary Graduate Program in Molecular and Cellular Biology (I.O.B.), University of Iowa Carver College of Medicine, Iowa City.
authors: Ilya O
authors: IO
authors: Blokhin
authors: From the Departments of Internal Medicine (H.J., M.A.G., I.O.B., K.M.W., A.K.C., C.D.S., S.R.L.) and Pharmacology (P.K., H.L.K., C.D.S.), Interdisciplinary Graduate Program in Molecular and Cellular Biology (I.O.B.), University of Iowa Carver College of Medicine, Iowa City.
authors: Katina M
authors: KM
authors: Wilson
authors: From the Departments of Internal Medicine (H.J., M.A.G., I.O.B., K.M.W., A.K.C., C.D.S., S.R.L.) and Pharmacology (P.K., H.L.K., C.D.S.), Interdisciplinary Graduate Program in Molecular and Cellular Biology (I.O.B.), University of Iowa Carver College of Medicine, Iowa City.
authors: Pimonrat
authors: P
authors: Ketsawatsomkron
authors: From the Departments of Internal Medicine (H.J., M.A.G., I.O.B., K.M.W., A.K.C., C.D.S., S.R.L.) and Pharmacology (P.K., H.L.K., C.D.S.), Interdisciplinary Graduate Program in Molecular and Cellular Biology (I.O.B.), University of Iowa Carver College of Medicine, Iowa City.
authors: Anil K
authors: AK
authors: Chauhan
authors: From the Departments of Internal Medicine (H.J., M.A.G., I.O.B., K.M.W., A.K.C., C.D.S., S.R.L.) and Pharmacology (P.K., H.L.K., C.D.S.), Interdisciplinary Graduate Program in Molecular and Cellular Biology (I.O.B.), University of Iowa Carver College of Medicine, Iowa City.
authors: Henry L
authors: HL
authors: Keen
authors: From the Departments of Internal Medicine (H.J., M.A.G., I.O.B., K.M.W., A.K.C., C.D.S., S.R.L.) and Pharmacology (P.K., H.L.K., C.D.S.), Interdisciplinary Graduate Program in Molecular and Cellular Biology (I.O.B.), University of Iowa Carver College of Medicine, Iowa City.
authors: Curt D
authors: CD
authors: Sigmund
authors: From the Departments of Internal Medicine (H.J., M.A.G., I.O.B., K.M.W., A.K.C., C.D.S., S.R.L.) and Pharmacology (P.K., H.L.K., C.D.S.), Interdisciplinary Graduate Program in Molecular and Cellular Biology (I.O.B.), University of Iowa Carver College of Medicine, Iowa City. steven-lentz@uiowa.edu.
authors: Steven R
authors: SR
authors: Lentz
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D036904:Leukocyte Rolling; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D019007:P-Selectin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D014682:Vena Cava, Inferior / Q000378:metabolism / Q000473:pathology; D020246:Venous Thrombosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000906:Antibodies; D019007:P-Selectin; D047495:PPAR gamma; D012333:RNA, Messenger
keywords: P-selectin; endothelium; thrombosis