title: Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia.
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.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. sanjana-dayal@uiowa.edu
authors.forename: Sanjana
authors.initials: S
authors.lastname: Dayal
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chauhan
authors.forename: Melissa
authors.initials: M
authors.lastname: Jensen
authors.forename: Lorie
authors.initials: L
authors.lastname: Leo
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Lynch
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
authors.forename: Steven R
authors.initials: SR
authors.lastname: Lentz
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006403:Hematologic Tests; D006439:Hemodynamics / Q000235:genetics / Q000502:physiology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012307:Risk Factors; D012720:Severity of Illness Index; D013927:Thrombosis / Q000209:etiology*
chemical_list: D003541:Cystathionine beta-Synthase