Hong Jin1, Milena A Gebska1, Ilya O Blokhin1, Katina M Wilson1, Pimonrat Ketsawatsomkron1, Anil K Chauhan1, Henry L Keen1, Curt D Sigmund1, Steven R Lentz2. 1. 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. 2. 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.
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.
OBJECTIVE: We tested the hypothesis that endothelial peroxisome proliferator-activated receptor-γ protects against vascular thrombosis using a transgenicmouse 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-V290Mmice 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-V290Mmice (P<0.001). Plasma P-selectin and carotid artery P-selectin mRNA were elevated in E-V290Mmice (P<0.05). P-selectin-dependent leukocyte rolling on mesenteric venules was increased in E-V290Mmice compared with nontransgenic mice (53 ± 8 versus 25 ± 7 per minute; P=0.02). The shortened time to arterial occlusion in E-V290Mmice 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.
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