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.
|Bailey, Keith A; Haj, Fawaz G; Simon, Scott I et al. (2017) Atherosusceptible Shear Stress Activates Endoplasmic Reticulum Stress to Promote Endothelial Inflammation. Sci Rep 7:8196|
|Sun, Chongxiu; Simon, Scott I; Foster, Greg A et al. (2016) 11,12-Epoxyecosatrienoic acids mitigate endothelial dysfunction associated with estrogen loss and aging: Role of membrane depolarization. J Mol Cell Cardiol 94:180-188|
|Radecke, Christopher E; Warrick, Alexandra E; Singh, Gagan D et al. (2015) Coronary artery endothelial cells and microparticles increase expression of VCAM-1 in myocardial infarction. Thromb Haemost 113:605-16|
|Wang, Hongfeng; Weihrauch, Dorothee; Kersten, Judy R et al. (2015) Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats. Am J Physiol Heart Circ Physiol 309:H1130-40|
|Xu, Lu; Dai Perrard, Xiaoyuan; Perrard, Jerry L et al. (2015) Foamy monocytes form early and contribute to nascent atherosclerosis in mice with hypercholesterolemia. Arterioscler Thromb Vasc Biol 35:1787-97|
|Foster, Greg A; Xu, Lu; Chidambaram, Alagu A et al. (2015) CD11c/CD18 Signals Very Late Antigen-4 Activation To Initiate Foamy Monocyte Recruitment during the Onset of Hypercholesterolemia. J Immunol 195:5380-92|
|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|
|Wang, Ying I; Bettaieb, Ahmed; Sun, Chongxiu et al. (2013) Triglyceride-rich lipoprotein modulates endothelial vascular cell adhesion molecule (VCAM)-1 expression via differential regulation of endoplasmic reticulum stress. PLoS One 8:e78322|
|Kusunose, Jiro; Zhang, Hua; Gagnon, M Karen J et al. (2013) Microfluidic system for facilitated quantification of nanoparticle accumulation to cells under laminar flow. Ann Biomed Eng 41:89-99|
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