Vascular disease is the principal cause of death and disability among the 12 million patients in the United States with diabetes mellitus. Macrovascular complications, including myocardial infarction, stroke, and amputation are the leading cause of morbidity and mortality among this cohort of patients. Reduced bioavailability of endothelium-derived nitric oxide has been implicated in atherogenesis and may be a fundamental factor in the development of vascular disease in diabetes. Increased degradation of nitric oxide by reactive oxygen radicals and inhibition of nitric oxide synthase via activation of protein kinase C are each potential mechanisms to account for decreased nitric oxide. The sponsor's laboratory has demonstrated impaired endothelium-dependent vasodilation in patients with diabetes mellitus and in healthy, nondiabetic subjects with experimental hyperglycemia. Further experiments showed that vitamin C improved endothelium-dependent vasodilation implicating a culpable role for superoxide. The soluble, glutathione-dependent antioxidant pathway, responsible for detoxification of polar peroxides, is also adversely affected by hyperglycemia and may represent a specific physiologic mechanism causing, in part, the impaired endothelial function demonstrated in diabetes mellitus. This proposal will examine the effect of ebselen, a glutathione peroxidase mimetic on endothelial function in subjects with diabetes mellitus (type I and type II) and healthy, age-matched controls to determine if polar peroxides play an important role in endothelial dysfunction in diabetes. Hyperglycemia causes the up-regulation of protein kinase C isoform beta2 (PKC beta2) which may phosphorylate nitric oxide synthase, reducing its activity. This proposal will also examine the role of LY333531, a PKC beta2 inhibitor, on endothelium-dependent vasodilation in forearm resistance and conduit vessels in subjects with type I and type II diabetes mellitus and age-matched health controls.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL004169-02
Application #
6183658
Study Section
Special Emphasis Panel (ZHL1-CSR-F (M3))
Project Start
1999-08-13
Project End
2004-07-31
Budget Start
2000-08-15
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$130,464
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Beckman, Joshua A; Goldfine, Allison B; Leopold, Jane A et al. (2016) Ebselen does not improve oxidative stress and vascular function in patients with diabetes: a randomized, crossover trial. Am J Physiol Heart Circ Physiol 311:H1431-H1436
Sobieszczyk, Piotr; Borlaug, Barry A; Gornik, Heather L et al. (2010) Glycyrrhetinic acid attenuates vascular smooth muscle vasodilatory function in healthy humans. Clin Sci (Lond) 119:437-42
Beckman, Joshua A; Goldfine, Allison B; Goldin, Alison et al. (2010) Inhibition of protein kinase Cbeta does not improve endothelial function in type 2 diabetes. J Clin Endocrinol Metab 95:3783-7
Beckman, Joshua A; Preis, Ori; Ridker, Paul M et al. (2005) Comparison of usefulness of inflammatory markers in patients with versus without peripheral arterial disease in predicting adverse cardiovascular outcomes (myocardial infarction, stroke, and death). Am J Cardiol 96:1374-8
Beckman, Joshua A; Liao, James K; Hurley, Shauna et al. (2004) Atorvastatin restores endothelial function in normocholesterolemic smokers independent of changes in low-density lipoprotein. Circ Res 95:217-23
Beckman, Joshua A; Mehta, Rajendra H; Isselbacher, Eric M et al. (2004) Branch vessel complications are increased in aortic dissection patients with renal insufficiency. Vasc Med 9:267-70
Beckman, Joshua A; Goldfine, Allison B; Gordon, Mary Beth et al. (2003) Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol 285:H2392-8
Luscher, Thomas F; Creager, Mark A; Beckman, Joshua A et al. (2003) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part II. Circulation 108:1655-61
Beckman, Joshua A; Dunn, Kelly; Sasahara, Arthur A et al. (2003) Enoxaparin monotherapy without oral anticoagulation to treat acute symptomatic pulmonary embolism. Thromb Haemost 89:953-8
Creager, Mark A; Luscher, Thomas F; Cosentino, Francesco et al. (2003) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation 108:1527-32

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