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Endothelial PPAR-γ protects against vascular thrombosis by downregulating P-selectin expression. Arterioscler Thromb Vasc Biol 2015 Apr;35(4):838-44

Date

02/14/2015

Pubmed ID

25675995

Pubmed Central ID

PMC4376629

DOI

10.1161/ATVBAHA.115.305378

Scopus ID

2-s2.0-84933497865 (requires institutional sign-in at Scopus site)   33 Citations

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.

APPROACH AND 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.

Author List

Jin H, Gebska MA, Blokhin IO, Wilson KM, Ketsawatsomkron P, Chauhan AK, Keen HL, Sigmund CD, Lentz SR

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antibodies
Carotid Artery Diseases
Carotid Artery, Common
Disease Models, Animal
Down-Regulation
Endothelial Cells
Humans
Leukocyte Rolling
Male
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Neutrophils
P-Selectin
PPAR gamma
RNA, Messenger
Thrombosis
Time Factors
Vena Cava, Inferior
Venous Thrombosis