Regulation of Atherosclerosis by Matrikine Endotrophin

/Abstract Cardiovascular disease is the leading cause of mortality and disease burden in the world. Although pharmacological strategies now exist to prevent and treat cardiovascular diseases through lowering of plasma lipids, novel therapies are still urgently needed to address the residual risk of disease. Large, well-powered hu- man genetics studies of coronary artery disease (CAD) have demonstrated that there are many underlying ge- netic risk factors for CAD, which may serve as effective therapeutic targets. The Stitziel Lab has carried out a series of statistical genetics analyses to nominate extracellular matrix (ECM) protein COL6A3 as a causal pro- tein for CAD. Our analysis further suggests that increased levels of a C-terminal fragment of COL6A3 called endotrophin promotes CAD, and there is a growing body of evidence that this peptide promotes various meta- bolic and fibroinflammatory disorders. The overall objectives of this application are to (i) determine whether an- tibody-mediated neutralization or transgenic overexpression of endotrophin impacts progression of atheroscle- rosis in vivo and (ii) determine the mechanism by which endotrophin may signal to promote atherosclerosis. The central hypothesis of this proposal is that endotrophin promotes atherosclerosis by promoting myeloid cell recruitment to the plaque and inducing proatherogenic transcriptional changes in vascular cells. The rationale for this project is that its successful completion may nominate endotrophin as a causal driver of atherosclerosis in vivo and enhance our understanding of how ECM-derived peptides in the neointima can promote atheroscle- rosis. The central hypothesis will be tested through two specific aims: 1) Determine the impact of blocking en- dotrophin-mediated monocyte recruitment on atherosclerosis and 2) Determine the impact of vascular smooth muscle cell specific expression of endotrophin on atherosclerosis. Under the first aim, neutralizing antibodies for endotrophin will be used to evaluate the impact of blocking endotrophin-mediated signaling on atherosclero- sis. Additionally, established protocols for measuring monocyte trafficking to the atherosclerotic plaque will be employed to assess the effects that endotrophin exerts on promoting myeloid cell recruitment to the neointima. For the second aim, a novel smooth-muscle cell specific, doxycycline-inducible transgenic mice will be utilized the examine the impact of endotrophin overexpression in the vasculature. The research proposed in this appli- cation is significant because it seeks to establish the therapeutic potential of targeting an ECM-derived signal- ing molecule for atherosclerosis, which may be a promising therapeutic strategy orthogonal to currently exist- ing lipid-lowering strategies. Successful completion of this project will also provide me with the skills and expe- rience critical for my future as an independent physician-scientist investigating cardiovascular biology. Project Number: 1F30HL179947-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Paul Lee | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $36,673 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F10C-B (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F30HL17994701