Arterial Cell Reprogramming by Disturbed Flow and Hypercholesterolemia

Emory University, Atlanta GA

Investigators

Abstract

Project Summary/Abstract Atherosclerosis is a chronic inflammatory disease characterized by buildup of plaques in the arteries. It is the major underlying cause of myocardial infarction, ischemic stroke, and peripheral arterial disease, all of which are leading causes of death worldwide. Despite the prevalent use of statins that lower blood cholesterol levels, atherosclerosis remains the leading cause of death globally. Therefore, there is a crucial need to develop therapies that target non-lipid targets for atherosclerosis. Although its risk factors are systemic, atherosclerosis preferentially develops in arterial regions exposed to disturbed blood flow (d-flow), while those exposed to stable blood flow (s-flow) are protected. Using the mouse partial carotid ligation (PCL) model of atherosclerosis, the Jo Lab demonstrated that d-flow can induce atherosclerosis in the presence of hypercholesterolemia, but not with either alone. Even though these animal studies have shown the importance of d-flow on endothelial dyfucntion and consequently atherosclerosis development, the mechanisms underlying its development remain to be studied. To address this crucial gap in knowledge, the Jo Lab’s recent single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin-seq (scATAC-seq) studies have revealed that chronic exposure to d-flow causes Flow-Induced Reprogramming of Endothelial cells (ECs) (FIRE), including endothelial inflammation, endothelial-to-mesenchymal transition (EndMT), and the novel concept of endothelial- to-immune cell transition (EndIT) partially. Although d-flow alone could induce significant changes in the EC genes and FIRE, it requires additional risk factors such as hypercholesterolemia to induce atherosclerosis in mice. Therefore, it is hypothesized that a combination of d-flow and hypercholesterolemic induces complete endothelial reprogramming (FIRE), including full EndIT, leading to plaque development. To test this hypothesis, an scRNA-seq study on the murine PCL model of atherosclerosis was recently performed to compare the effects of d-flow alone, hypercholesterolemia alone, and d-flow + hypercholesterolemia. As expected, atherosclerotic plaques developed only under d-flow + hypercholesterolemia in mice. Preliminary scRNA-seq data analysis shows that ECs appear to undergo not only complete EndIT but also transition to foam cells, endothelial-to-foam cell transition (EndFT). To accomplish the goal of better understanding the flow-induced mechanisms of atherosclerosis pathophysiology for development of novel therapies, the following three aims are proposed for this F31 application: 1) Define arterial cell reprogramming, especially FIRE, that occurs during atherogenesis, 2) Validate FIRE in mouse and human arteries, and 3) Screen d-flow-sensitive genes of FIRE as potential novel therapeutic targets for atherosclerosis. Addressing these aims will provide novel insights into the mechanism of flow-induced atherogenesis and identification of new therapeutic targets for its prevention. Overall, trainings under the mentorship of Dr. Hanjoong Jo at Emory University and Georgia Tech will enable Christian Park to become an innovative and independent cardiovascular researcher well-equipped to conduct impactful studies.