Endothelial PPAR-γ Protects Against Vascular Thrombosis by Downregulating P-Selectin Expression. Issue 4 (April 2015)

• Record Type: Journal Article
• 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.
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 35:Issue 4(2015)
• Publication Date: 2015-04
• Subjects: endothelium -- P-selectin -- thrombosis; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.115.305378
• Languages: English
• ISSNs: 1079-5642

Abstract

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. Abstract : Supplemental Digital Content is available in the text.