Prothrombotic effects of hyperhomocysteinemia and hypercholesterolemia in ApoE-deficient mice.
OBJECTIVE
We tested the hypothesis that hyperhomocysteinemia and hypercholesterolemia promote arterial thrombosis in mice.


RESULTS
Male apolipoprotein E (Apoe)-deficient mice were fed one of four diets: control, hyperhomocysteinemic (HH), high fat (HF), or high fat/hyperhomocysteinemic (HF/HH). Total cholesterol was elevated 2-fold with the HF or HF/HH diets compared with the control or HH diets (P<0.001). Plasma total homocysteine (tHcy) was elevated (12 to 15 micromol/L) with the HH or HF/HH diets compared with the control or HF diets (4 to 6 micromol/L; P<0.001). Aortic sinus lesion area correlated strongly with total cholesterol (P<0.001) but was independent of tHcy. At 12 weeks of age, the time to thrombotic occlusion of the carotid artery after photochemical injury was >50% shorter in mice fed the HF diets, with or without hyperhomocysteinemia, compared with the control diet (P<0.05). At 24 weeks of age, carotid artery thrombosis was also accelerated in mice fed the HH diet (P<0.05). Endothelium-dependent nitric oxide-mediated relaxation of carotid artery rings was impaired in mice fed the HF, HH, or HF/HH diets compared with the control diet (P<0.05).


CONCLUSIONS
Hyperhomocysteinemia and hypercholesterolemia, alone or in combination, produce endothelial dysfunction and increased susceptibility to thrombosis in Apoe-deficient mice.
Wilson
Katina M
KM
Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
McCaw
Ryan B
RB
Leo
Lorie
L
Arning
Erland
E
Lhoták
Sárka
S
Bottiglieri
Teodoro
T
Austin
Richard C
RC
Lentz
Steven R
SR
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D001835:Body Weight / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D004198:Disease Susceptibility / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000502:physiology; D006710:Homocysteine / Q000097:blood; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D020138:Hyperhomocysteinemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008715:Methionine / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000502:physiology; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*
D001057:Apolipoproteins E; D006710:Homocysteine; D002784:Cholesterol; D008715:Methionine