Type 2 diabetes mellitus is a major and increasingly prevalent risk factor for cardiovascular disease. Risk persists despite intensive risk factor and glucose control. A key mechanism in diabetic vascular disease is the development of endothelial dysfunction. An improved understanding ofthe mechanisms of endothelial dysfunction in diabetes could stimulate new approaches for patient management. Prior experimental studies link mitochondrial dysfunction to the pathogenesis of diabetic vascular disease. Elevated glucose and free fatty acid levels stimulate mitochondrial production of reactive oxygen species (ROS) and impair biogenesis and dynamics. These conditions reduce nitric oxide availability and activate endothelial cells. Although abnormalities of mitochondrial function have been observed in skeletal muscle from patients, the connections between mitochondrial dysfunction and vascular disease remain pooriy understood in human diabetes. We have developed methodology to study specific aspects of mitochondrial function in freshly isolated vascular tissue (venous endothelial cells and arterioles from subcutaneous fat) and in more accessible blood mononuclear cells. Our preliminary studies show increased mitochondrial ROS, decreased mitochondrial mass, and loss of mitochondrial networks that relate to endothelial dysfunction.
In Aim 1, we will correlate mitochondrial function in isolated endothelial cells and mononuclear cells to endothelial function in the forearm of 200 patients and controls.
In Aim 2, we will investigate the mechanistic links between mitochondrial and endothelial dysfunction by isolating arterioles from subcutaneous fat and use organ chamber methodology and video microscopy to measure the effects of specific mitochondrial agonists/antagonists on endothelium-dependent vasodilation.
In Aim 3, we will determine whether an intervention designed to increase mitochondrial biogenesis and dynamics (resveratrol) has favorable effects on our measures of endothelial and mitochondrial function in a randomized, placebo-controlled crossover study in 50 patients with diabetes mellitus. Our proposed studies fit well with the overall theme ofthe Program Project, and we expect to obtain novel information about the contribution of mitochondrial dysfunction to vascular injury that will bring us closer to identifying optimal treatment strategies to reduce cardiovascular risk in diabetes.

Public Health Relevance

Cardiovascular disease in diabetes mellitus is a major public health problem, accounting for 14% of health care expenditures in the United States. According to a recent report, 12% of Americans over age 20 have diagnosed or undiagnosed diabetes and the prevalence is increasing. Patients with diabetes have 2- to 4-fold higher risk for cardiovascular events, and thus, the current project will address the compelling need for an imorovad understanding of the mechanisms of cardiovascular risk in diabetes

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL081587-08
Application #
8438334
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
8
Fiscal Year
2013
Total Cost
$530,350
Indirect Cost
$172,052
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Maruyama, Sonomi; Nakamura, Kazuto; Papanicolaou, Kyriakos N et al. (2016) Follistatin-like 1 promotes cardiac fibroblast activation and protects the heart from rupture. EMBO Mol Med 8:949-66
Nakamura, Kazuto; Sano, Soichi; Fuster, José J et al. (2016) Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury. J Biol Chem 291:2566-75
Fetterman, Jessica L; Holbrook, Monica; Flint, Nir et al. (2016) Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling. Atherosclerosis 247:207-17
Krzywanski, David M; Moellering, Douglas R; Westbrook, David G et al. (2016) Endothelial Cell Bioenergetics and Mitochondrial DNA Damage Differ in Humans Having African or West Eurasian Maternal Ancestry. Circ Cardiovasc Genet 9:26-36
Tampakakis, Emmanouil; Tabit, Corey E; Holbrook, Monika et al. (2016) Intravenous Lipid Infusion Induces Endoplasmic Reticulum Stress in Endothelial Cells and Blood Mononuclear Cells of Healthy Adults. J Am Heart Assoc 5:
Fetterman, Jessica L; Holbrook, Monica; Westbrook, David G et al. (2016) Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease. Cardiovasc Diabetol 15:53
Bretón-Romero, Rosa; Feng, Bihua; Holbrook, Monika et al. (2016) Endothelial Dysfunction in Human Diabetes Is Mediated by Wnt5a-JNK Signaling. Arterioscler Thromb Vasc Biol 36:561-9
Lee, Richard T; Walsh, Kenneth (2016) The Future of Cardiovascular Regenerative Medicine. Circulation 133:2618-25
Fuster, José J; Ouchi, Noriyuki; Gokce, Noyan et al. (2016) Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease. Circ Res 118:1786-807
Mohandas, Appesh; Suboc, Tisha B; Wang, Jingli et al. (2015) Mineralocorticoid exposure and receptor activity modulate microvascular endothelial function in African Americans with and without hypertension. Vasc Med 20:401-8

Showing the most recent 10 out of 165 publications