Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia

Sanjana Dayal; Anil K Chauhan; Melissa Jensen; Lorie Leo; Cynthia M Lynch; Frank M Faraci; Warren D Kruger; Steven R Lentz

doi:10.1182/blood-2011-09-380568

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Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia

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Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia

Sanjana Dayal, Anil K Chauhan, Melissa Jensen, Lorie Leo, Cynthia M Lynch, Frank M Faraci, Warren D Kruger and Steven R Lentz

Blood, Vol.119(13), pp.3176-3183

03/29/2012

DOI: 10.1182/blood-2011-09-380568

PMCID: PMC3321876

PMID: 22186991

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Abstract

Hyperhomocysteinemia confers a high risk for thrombotic vascular events, but homocysteine-lowering therapies have been ineffective in reducing the incidence of secondary vascular outcomes, raising questions regarding the role of homocysteine as a mediator of cardiovascular disease. Therefore, to determine the contribution of elevated homocysteine to thrombosis susceptibility, we studied Cbs −/− mice conditionally expressing a zinc-inducible mutated human CBS (I278T) transgene. Tg-I278T Cbs −/− mice exhibited severe hyperhomocysteinemia and endothelial dysfunction in cerebral arterioles. Surprisingly, however, these mice did not display increased susceptibility to arterial or venous thrombosis as measured by photochemical injury in the carotid artery, chemical injury in the carotid artery or mesenteric arterioles, or ligation of the inferior vena cava. A survey of hemostatic and hemodynamic parameters revealed no detectible differences between control and Tg-I278T Cbs −/− mice. Our data demonstrate that severe elevation in homocysteine leads to the development of vascular endothelial dysfunction but is not sufficient to promote thrombosis. These findings may provide insights into the failure of homocysteine-lowering trials in secondary prevention from thrombotic vascular events.

Thrombosis and Hemostasis

Details

Title: Subtitle: Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia
Creators: Sanjana Dayal - Departments of
Anil K Chauhan - Departments of
Melissa Jensen - Departments of
Lorie Leo - Departments of
Cynthia M Lynch - Departments of
Frank M Faraci - Departments of
Warren D Kruger - Fox Chase Cancer Center, Philadelphia, PA
Steven R Lentz - Departments of
Resource Type: Journal article
Publication Details: Blood, Vol.119(13), pp.3176-3183
Publisher: American Society of Hematology; Washington, DC
DOI: 10.1182/blood-2011-09-380568
PMID: 22186991
PMCID: PMC3321876
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: HL062984; HL063943; NS024621 / National Institutes of Health
Language: English
Date published: 03/29/2012
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040012002771

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