Vascular endothelial function is a critical determinant of cardiovascular risk in obesity. We have recently shown that a proinflammatory fat phenotype is coupled with insulin resistance and vascular dysfunction. While shared inflammatory mechanisms underlie both atherosclerosis and adipose remodeling, little is known about the adverse vascular consequences of adipose inflammation or how this relationship is modulated by large-scale weight loss.
In aim 1, we propose to characterize the relationship between adipose tissue phenotype and local microvascular function in fat. In 200 obese individuals, we will biopsy fat depots during bariatric surgery and assess depot-speciflc inflammatory activity by quantifying adipocytokine expression, macrophage density, macrophage polarization (M1/M2) using immunohistochemistry, flowcytometry, and rt-PCR. These findings will be related to endothelial vasodilator function of small arterioles isolated from adipose tissue. We hypothesize that blood vessels from more inflamed fat will exhibit a proatherogenic profile.
In aim 2, we will determine whether microvascular function in fat correlates with systemic vascular function by examining brachial artery flow-mediated dilation and reactive hyperemia prior to bariatric surgery in all subjects from aim 1. We will relate these measures of systemic macro- and microvascular function to vascular phenotype and inflammation in adipose tissue. We hypothesize that arterial dysfunction in fat will be associated with a generalized systemic state of vascular impairment.
In aim 3, we propose to determine the effects of extensive weight loss following bariatric surgery on adipose phenotype and local and systemic vascular function. We will repeat vascular studies and biopsy subcutaneous fat at 3 months and 1-year after bariatric surgery in the same 200 subjects. We hypothesize that weight reduction will improve vascular health and that reduced inflammatory burden will relate more closely to arterial phenotype than the magnitude of weight loss. The proposed studies are likely to yield novel and important information about the mechanisms of obesity-induced cardiovascular disease in a group of very obese subjects (BMI S35 kg/m2) where very limited cardiovascular data are currently available.
Obesity has emerged as the most critical health care problem in the US. Currently over 65% of adults in the US are overweight and the prevalence of severe obesity has more than tripled in the last decade with no signs of slowing. Cardiovascular disease is the leading cause of death in this populafion and this project seeks to investigate mechanisms of obesity-related vascular disease as an area of high priority research.
|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, JosÃ© 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|
|BretÃ³n-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, JosÃ© 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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