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

Hong Jin; Milena A Gebska; Ilya O Blokhin; Katina M Wilson; Pimonrat Ketsawatsomkron; Anil K Chauhan; Henry L Keen; Curt D Sigmund; Steven R Lentz

doi:10.1161/ATVBAHA.115.305378

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

Journal article

Open access

Peer reviewed

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

Hong Jin, Milena A Gebska, Ilya O Blokhin, Katina M Wilson, Pimonrat Ketsawatsomkron, Anil K Chauhan, Henry L Keen, Curt D Sigmund and Steven R Lentz

Arteriosclerosis, thrombosis, and vascular biology, Vol.35(4), pp.838-844

04/2015

DOI: 10.1161/ATVBAHA.115.305378

PMCID: PMC4376629

PMID: 25675995

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Abstract

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.

Carotid Artery Diseases - prevention & control

P-Selectin - metabolism

Humans

Leukocyte Rolling

Male

PPAR gamma - metabolism

RNA, Messenger - metabolism

Venous Thrombosis - immunology

Time Factors

Carotid Artery Diseases - pathology

Vena Cava, Inferior - pathology

Venous Thrombosis - prevention & control

Thrombosis - prevention & control

Carotid Artery Diseases - metabolism

Neutrophils - metabolism

Disease Models, Animal

P-Selectin - immunology

PPAR gamma - genetics

Carotid Artery Diseases - immunology

P-Selectin - antagonists & inhibitors

Carotid Artery, Common - metabolism

Endothelial Cells - metabolism

Down-Regulation

Mice, Inbred C57BL

Venous Thrombosis - metabolism

Neutrophils - immunology

Thrombosis - immunology

Mice, Transgenic

Vena Cava, Inferior - metabolism

P-Selectin - genetics

Antibodies - pharmacology

Endothelial Cells - immunology

Thrombosis - pathology

Thrombosis - metabolism

Animals

Carotid Artery Diseases - genetics

Carotid Artery, Common - pathology

Thrombosis - genetics

Venous Thrombosis - genetics

Mutation

Venous Thrombosis - pathology

Endothelial Cells - pathology

Endothelial Cells - drug effects

Details

Title: Subtitle: Endothelial PPAR-γ protects against vascular thrombosis by downregulating P-selectin expression
Creators: Hong Jin - 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
Milena A Gebska - 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
Ilya O Blokhin - 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
Katina M Wilson - 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
Pimonrat Ketsawatsomkron - 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
Anil K Chauhan - 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
Henry L Keen - 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
Curt D Sigmund - 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 R Lentz - 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
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.35(4), pp.838-844
DOI: 10.1161/ATVBAHA.115.305378
PMID: 25675995
PMCID: PMC4376629
ISSN: 1079-5642
eISSN: 1524-4636
Grant note: HL084207 / NHLBI NIH HHS R01 HL061446 / NHLBI NIH HHS HL118742 / NHLBI NIH HHS R01 HL063943 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS R37 HL048058 / NHLBI NIH HHS HL063943 / NHLBI NIH HHS HL048058 / NHLBI NIH HHS R01 HL118742 / NHLBI NIH HHS HL061446 / NHLBI NIH HHS T32 HL007344 / NHLBI NIH HHS R01 HL048058 / NHLBI NIH HHS HL118246 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS R01 HL118246 / NHLBI NIH HHS HL062984 / NHLBI NIH HHS
Language: English
Date published: 04/2015
Academic Unit: Molecular Physiology and Biophysics; Hematology, Oncology, and Blood & Marrow Transplantation; Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984094521602771

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