Endothelial PPAR-γ protects against vascular thrombosis by downregulating P-selectin expression

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 35; no. 4; pp. 838 - 844
• Main Authors: Jin, Hong, Gebska, Milena A, Blokhin, Ilya O, Wilson, Katina M, Ketsawatsomkron, Pimonrat, Chauhan, Anil K, Keen, Henry L, Sigmund, Curt D, Lentz, Steven R
• Format: Journal Article
• Language: English
• Published: United States 01.04.2015
• Subjects: Animals; Antibodies - pharmacology; Carotid Artery Diseases - genetics; Carotid Artery Diseases - immunology; Carotid Artery Diseases - metabolism; Carotid Artery Diseases - pathology; Carotid Artery Diseases - prevention & control; Carotid Artery, Common - metabolism; Carotid Artery, Common - pathology; Disease Models, Animal; Down-Regulation; Endothelial Cells - drug effects; Endothelial Cells - immunology; Endothelial Cells - metabolism; Endothelial Cells - pathology; Humans; Leukocyte Rolling; Male; Medicin och hälsovetenskap; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neutrophils - immunology; Neutrophils - metabolism; P-Selectin - antagonists & inhibitors; P-Selectin - genetics; P-Selectin - immunology; P-Selectin - metabolism; PPAR gamma - genetics; PPAR gamma - metabolism; RNA, Messenger - metabolism; Thrombosis - genetics; Thrombosis - immunology; Thrombosis - metabolism; Thrombosis - pathology; Thrombosis - prevention & control; Time Factors; Vena Cava, Inferior - metabolism; Vena Cava, Inferior - pathology; Venous Thrombosis - genetics; Venous Thrombosis - immunology; Venous Thrombosis - metabolism; Venous Thrombosis - pathology; Venous Thrombosis - prevention & control; endothelium; P-selectin; thrombosis
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.115.305378

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. 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. 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.