It is widely recognized that the endothelium is affected by the metabolic state of the organism, and endothelial function can also influence systemic metabolism. This program project renewal application brings together five productive project leaders who have a long history of collaboration to investigate mechanisms that underlie how the endothelium is both affected by and contributes to metabolic homeostasis. Project 1 will examine the mechanism by which endothelial cells switch from aerobic respiration to anaerobic glycolysis under conditions that stimulate vascular growth (i.e. hypoxia and pseudo-hypoxia) by focusing on a HIF1a-regulated microRNA that regulates the expression of mitochondrial respiratory complex proteins. Project 2 will examine mechanisms of redox regulation of cell signaling in vascular function and how these processes are perturbed by endothelial cell exposure to oxidants and reactive lipids that are associated with inflammation and metabolic disease. Project 3 will examine the functional interplay between endothelial function and inflammation in adipose tissue and assess how these processes influence systemic metabolism by focusing on mouse models that over- and under-express the adipocyte-derived cytokine adiponectin. Project 4 will also examine the interrelationship between the endothelium and inflammation in fat by measuring microvascular function and inflammatory markers in the fat of obese individuals before and after extensive weight loss resulting from bariatric surgery. Project 5 will examine the role of mitochondrial homeostasis in endothelial and inflammatory cells isolated from patients with Type 2 diabetes mellitus. This conceptually cohesive program focuses on an under-explored, yet clinically important, area of endothelial cell biology. With these proposed studies, we hope develop a better understanding of how endothelium functions at the interface of cardiovascular disease and metabolic dysfunction.

Public Health Relevance

Obesity and diabetes have a devastating impact on how blood vessels function, leading to the development of cardiovascular diseases. This program project grant invloves research from 5 laboratories that will study how metabolic disease interrelates to vascular disease. These studies will be conducted in cultured cells, genetically-engineered mice and in patient populations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL081587-09
Application #
8627633
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Ershow, Abby
Project Start
2005-09-30
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
9
Fiscal Year
2014
Total Cost
$1,964,008
Indirect Cost
$728,999
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
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

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