Macrophage accumulation at the site of inflammation is essential for the development of different inflammatory diseases including obesity, diabetes and atherosclerosis. Lipid peroxidation is an important pathophysiological mechanism that is facilitated by inflammation and contributes to its further development. Yet, the link between lipid oxidation and macrophage accumulation is not fully understood. The overall goal of this proposal is to determine the mechanism of macrophage accumulation in the inflamed vascular wall during atherosclerosis. The objective is to establish the link between carboxyethylpyrrole (CEP) generation during DHA oxidation and alphaDbeta2 integrin-mediated macrophage retention at the site of inflammation. We hypothesize that: 1) inflammation stimulates phospholipid oxidation in the atherosclerotic lesions that results in the generation of CEP adducts with extracellular matrix proteins, and 2) these CEP-modified proteins serve as inflammatory-specific ligands for integrin alphaDbeta2-mediated macrophage retention within the inflamed vascular wall during atherosclerosis. Guided by our published results and strong preliminary data, this hypothesis will be tested by pursuing three Specific Aims: 1. To characterize a potential role of CEP in alphaDbeta2-mediated retention of M1-polarized macrophages in 3D matrix in vitro ; 2. To identify potential inhibitors of CEP-integrin alphaDbeta2 interaction; 3. To test the inhibitors of CEP-mediated macrophage retention in the model of atherosclerosis. The significance of our study resides in providing new insights into the mechanism of macrophage retention by focusing on the contribution of DHA to the inflammatory response. The proposal is innovative because the establishing the product of DHA oxidation, CEP, as a new ligand for macrophage retention will answer the fundamental question regarding the potential pro-inflammatory functions of DHA that may surpass the protective contribution of other DHA-derived products. The information obtained from the proposed studies will provide a new strategy for the treatment of chronic inflammatory diseases. The blocking of CEP in peripheral tissues during atherogenesis can prevent macrophage accumulation and the development of chronic inflammation. The development of anti-inflammatory treatments is an objective of our further investigations.
|Program type||AHA Institutional Research Enhancement Award (AIRE|
|Effective start/end date||01/01/2020 → 12/31/2021|