This competitive renewal is focused on atherosclerosis, the primary cause of mortality in Western society. Our studies and others reveal that arterial plaque formation closely correlates with visceral obesity and concomitant high levels of circulating triglyceride rich lipoproteins (TGRL), especially associated with diets high in saturated fat. Over the tenure of this grant, we have developed an ex-vivo model of early inflammatory events of atherogenesis by studying blood monocytes and TGRL isolated postprandial from plasma of subjects ranging from healthy to obese and hypertriglyceridemic. By examining their interaction with low passage cultured human aortic endothelial cells (HAEC), we have reported that acute exposure to TGRL augmented cytokine- induced VCAM-1 expression and monocyte recruitment under shear stress. In subjects exhibiting high cardiovascular risk (i.e. high postprandial TGRL and abdominal obesity) we detected increased foamy monocytes in blood and correlated this with integrin activation and arrest to VCAM-1, as quantified in our vascular mimetic shear flow assay. These data provide a framework for quantifying an individual's atherogenic susceptibility. Our primary hypothesis is that we can delineate the metabolic pathways that go awry and correlate these with biomarkers of endothelial and monocyte inflammation measured ex vivo in order to provide valuable clinical insight in assessing an individual's risk for developing inflammation-mediated coronary artery disease. A systems bioengineering approach is applied to study metabolic and biomechanical responses at the cell and molecular scale using real time imaging and novel microfluidic technology in three specific aims: 1) Quantify an individual's metabolic profile following a high-fat meal in terms of the inflammatory capacity of their TGRL. 2) Delineate how TGRL signaling pathways regulate an atherogenic profile in aortic endothelium. 3) Identify the earliest events linked to hypertriglyceridemia and obesity that increase monocyte proclivity to arrest on atherogenic endothelium using a lab-on-a-chip assay. Our overall goal is to develop assays that pinpoint the extent to which dietary lipoproteins from healthy and metabolic syndrome subjects are exerting pro- inflammatory effects that shift the balance from healthy to atherogenic vasculature.
This project extends our studies of how dietary lipids affect inflammation in arteries. The interaction of lipoprotein particles and their metabolites with blood monocytes and endothelial cells that line the vessel wall becomes dysregulated during heart disease. A bioengineering approach is applied to gauge an individual's inflammatory risk for cardiovascular disease in response to a high-fat diet and in patients from the clinic. These studies will provide personalized measures to help guide the development of novel strategies to prevent, diagnose and treat heart disease.
|Tarbell, John M; Simon, Scott I; Curry, Fitz-Roy E (2014) Mechanosensing at the vascular interface. Annu Rev Biomed Eng 16:505-32|
|Foster, Greg A; Gower, R Michael; Stanhope, Kimber L et al. (2013) On-chip phenotypic analysis of inflammatory monocytes in atherogenesis and myocardial infarction. Proc Natl Acad Sci U S A 110:13944-9|
|DeVerse, J Sherrod; Sandhu, Angad S; Mendoza, Natalie et al. (2013) Shear stress modulates VCAM-1 expression in response to TNF-? and dietary lipids via interferon regulatory factor-1 in cultured endothelium. Am J Physiol Heart Circ Physiol 305:H1149-57|
|DeVerse, J Sherrod; Bailey, Keith A; Jackson, Kaleena N et al. (2012) Shear stress modulates RAGE-mediated inflammation in a model of diabetes-induced metabolic stress. Am J Physiol Heart Circ Physiol 302:H2498-508|
|Gower, R Michael; Wu, Huaizhu; Foster, Greg A et al. (2011) CD11c/CD18 expression is upregulated on blood monocytes during hypertriglyceridemia and enhances adhesion to vascular cell adhesion molecule-1. Arterioscler Thromb Vasc Biol 31:160-6|
|Wang, Ying I; Schulze, John; Raymond, Nadine et al. (2011) Endothelial inflammation correlates with subject triglycerides and waist size after a high-fat meal. Am J Physiol Heart Circ Physiol 300:H784-91|
|Glaser, Drew E; Gower, Robert M; Lauer, Nicholas E et al. (2011) Functional characterization of embryonic stem cell-derived endothelial cells. J Vasc Res 48:415-28|
|Wu, Huaizhu; Gower, R Michael; Wang, Hong et al. (2009) Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation 119:2708-17|