Recent studies have emphasized that mitochondria in endothelial cells play an important role in signaling in response to environmental cues, including nutrient excess. Mitochondrial signaling is mediated in large part by regulated production of reactive oxygen species (ROS) by components of the electron transport chain. Physiological signaling depends on control of membrane potential by uncoupling protein-2 (UCP2) and preserved integrity of mitochondrial proteins and mtDNA via an appropriate balance between mitochondrial fission and fusion to maintain normal mitochondrial networks (mitochondrial dynamics). Obesity is associated with an imbalance between energy supply and demand in the body. We hypothesize that chronic energy excess creates a vicious cycle of increased ROS that triggers mitochondrial fragmentation and an inadequate UCP-2 response that further increases ROS and impairs endothelial function. In this project, we will relate nitric oxide signaling and endothelium-dependent vasodilation to relevant aspects of mitochondrial function in freshly isolated arterial endothelial cells from obese patients and from healthy volunteers exposed to two human models of energy excess. Our preliminary data show impaired eNOS signaling, decreased UCP2, mitochondrial fragmentation, and an increase in the fission protein Fis1 in endothelial cells collected from obese patients. Our project has 3 specific aims:
For Aim 1, we will collect arterial endothelial cells from obese patients and measure mitochondrial ROS, network extent, and expression of UCP-2, Mfn2, and Fis1 and relate the findings to endothelium- dependent vasodilation in the arm and to eNOS activation in the freshly isolated cells. We will also determine whether silencing Fis1 or over-expressing UCP-2 or Mfn2 restores eNOS activation.
In Aim 2, we will determine whether altered dynamics and UCP-2 contribute to endothelial dysfunction induced by Intralipid infusion (energy excess), and in Aim 3, we will determine whether these mechanisms contribute to endothelial dysfunction induced by bed rest (decreased energy demand). We anticipate increased ROS, network fragmentation, decreased UCP2, and impaired eNOS activation in cells from obese patients. If Intralipid and bed rest induce an obese endothelial phenotype and if over- expressing UCP-2 or silencing Fis1 reverses endothelial dysfunction, we will have strong evidence that these mechanisms contribute to the pathogenesis of endothelial dysfunction in human obesity.
The ongoing obesity epidemic is responsible for recent increases in the prevalence of diabetes mellitus and cardiovascular disease. This project seeks to improve our understanding of the mechanisms of obesity-associated cardiovascular disease and could stimulate new approaches for prevention and management.
|Bretón-Romero, Rosa; Hamburg, Naomi M (2017) Every PACE Counts: Learning About Blood Cells and Blood Flow in Peripheral Artery Disease. Circulation 135:1429-1431|
|Zuriaga, María A; Fuster, José J; Farb, Melissa G et al. (2017) Activation of non-canonical WNT signaling in human visceral adipose tissue contributes to local and systemic inflammation. Sci Rep 7:17326|
|Brant, Luisa C C; Wang, Na; Ojeda, Francisco M et al. (2017) Relations of Metabolically Healthy and Unhealthy Obesity to Digital Vascular Function in Three Community-Based Cohorts: A Meta-Analysis. J Am Heart Assoc 6:|
|Fetterman, Jessica L; Liu, Chunyu; Mitchell, Gary F et al. (2017) Relations of mitochondrial genetic variants to measures of vascular function. Mitochondrion :|
|Cooper, Leroy L; Palmisano, Joseph N; Benjamin, Emelia J et al. (2016) Microvascular Function Contributes to the Relation Between Aortic Stiffness and Cardiovascular Events: The Framingham Heart Study. Circ Cardiovasc Imaging 9:|
|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|
|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|
|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:|
|Bretón-Romero, Rosa; Wang, Na; Palmisano, Joseph et al. (2016) Cross-Sectional Associations of Flow Reversal, Vascular Function, and Arterial Stiffness in the Framingham Heart Study. Arterioscler Thromb Vasc Biol 36:2452-2459|
|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|
Showing the most recent 10 out of 20 publications