Modest elevations in plasma homocysteine are associated with an increased risk of atherosclerotic disease. Impaired endothelial vasodilator function appears to play an important role in progression and complications of atherosclerosis. Thus, homocysteine-induced endothelial dysfunction is a plausible mechanism for predisposition to atherosclerosis. In previous studies funded by this R01, we have demonstrated that induction of experimental hyperhomocysteinemia by methionine loading rapidly produces profound endothelial dysfunction in human subjects, which can be reversed by anti-oxidants. We have also shown that high protein diets cause post-prandial hyperhomocysteinemia. In addition, we have developed a series of novel pharmacological models to characterize endothelial mediators and several putative mechanisms of oxidant stress. We therefore plan to test the following specific aims: 1) To explore endothelial mediators affected by experimental hyperhomocysteinemia in humans (specifically test the hypothesis that homocysteine selectively impairs nitric oxide activity and that there is compensatory upregulation of endothelium-derived hyperpolarizing factor); 2) To test potential oxidant mechanisms underlying the endothelial dysfunction (specifically xanthine oxidase, cyclooxygenase and inducible nitric oxide synthase); and 3) To examine the effect of dietary interventions with varying protein and folate intakes on plasma homocysteine and endothelial function, particularly in subjects with genetic (MTHFR mutation) or renal (transplant recipients) predisposition to hyperhomocysteinemia. Endothelial function will be tested in conduit and resistance vessels in vivo using flow mediated vasodilatation and forearm blood flow responses to intra-arterial administration of vasoactive agents. This patient-orientated research should lead to new understanding of the pathophysiological mechanisms linking homocysteine to vascular disease in humans. The results may also suggest novel potential therapeutic approaches to be tested in future outcome trials.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058972-07
Application #
6739025
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Program Officer
Ershow, Abby
Project Start
1998-05-01
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
7
Fiscal Year
2004
Total Cost
$368,750
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Dopp, John M; Agapitov, Alexei V; Sinkey, Christine A et al. (2013) Sildenafil increases sympathetically mediated vascular tone in humans. Am J Hypertens 26:762-9
Fiedorowicz, Jess G; Haynes, William G (2010) Cholesterol, mood, and vascular health: Untangling the relationship: Does low cholesterol predispose to depression and suicide, or vice versa? Curr Psychiatr 9:17-A
Guthikonda, Sasidhar; Sinkey, Christine A; Haynes, William G (2007) What is the most appropriate methodology for detection of conduit artery endothelial dysfunction? Arterioscler Thromb Vasc Biol 27:1172-6
Dokras, Anuja; Jagasia, Dinesh H; Maifeld, Michelle et al. (2006) Obesity and insulin resistance but not hyperandrogenism mediates vascular dysfunction in women with polycystic ovary syndrome. Fertil Steril 86:1702-9
Al-Shaer, Moutasim H; Choueiri, Nabil E; Correia, Marcelo L G et al. (2006) Effects of aging and atherosclerosis on endothelial and vascular smooth muscle function in humans. Int J Cardiol 109:201-6
Correia, Marcelo L G; Haynes, William G (2006) A role for plasminogen activator inhibitor-1 in obesity: from pie to PAI? Arterioscler Thromb Vasc Biol 26:2183-5
Al-Shaer, Moutasim H; Raghuveer, Geetha; Browning, Roger et al. (2005) Effect of hyperhomocysteinemia induced by methionine administration on flow-mediated dilatation of the brachial artery in healthy subjects. Am J Cardiol 95:428-30
Lentz, Steven R; Haynes, William G (2004) Homocysteine: is it a clinically important cardiovascular risk factor? Cleve Clin J Med 71:729-34
Guthikonda, Sashi; Sinkey, Christine; Barenz, Therese et al. (2003) Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers. Circulation 107:416-21
Haynes, William G (2003) Triglyceride-rich lipoproteins and vascular function. Arterioscler Thromb Vasc Biol 23:153-5

Showing the most recent 10 out of 17 publications