PPAR-Mediated Inhibition of Vascular Remodeling

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DESCRIPTION (provided by applicant): PPAR? (peroxisome proliferator-activated receptor) is a ligand-activated transcription factor that regulates glucose and lipid metabolism. Drugs activating PPAR? significantly improve metabolic profiles in diabetic patients, and consequently also their cardiovascular function. More recently, it was recognized that PPAR? ligands inhibit inflammatory diseases in several mouse models. However, the role of PPAR? in immune mechanisms involved in the pathogenesis of atherosclerosis and vascular remodeling has not been addressed. We tested the in vivo effects of two PPAR3 ligands, 15 deoxy-prostaglandin-J2 (15-d-PGJ2) and ciglitazone, on T cell induced remodeling of human artery in vivo in our humanized mouse model. PPAR? ligands prevented remodeling, and this protection was abrogated by simultaneous treatment with the PPAR? antagonist, GW9662. Since the interactions between endothelial cells (EC) and lymphocytes initiate vascular inflammation, we investigated the expression of PPAR? in these primary human cells. Most remarkable were the differences in expression of PPAR? in T cell subpopulations, where the highest expression was observed in activated regulatory T cells. This suggests that PPAR? ligands may inhibit inflammatory responses via activating suppressive functions of regulatory T cells. Given that PPAR? ligands have both PPAR? dependent, as well as independent effects, we propose to combine molecular and pharmacological approaches to dissect the role of PPAR? in the interactions between human EC and T cells both in vitro and in vivo. We hypothesize that the inhibitory effects of PPAR? activation on arterial remodeling may be mediated via activating regulatory T cells and via maintaining EC quiescent. The specific aims of this project are: first, to determine the role of PPAR? in remodeling of human artery segments grafted into SCID mice after reconstitution with alloreactive PBMC and/or CD34 progenitors; second, to establish the functional roles of PPAR? in human EC and T cell subsets by genetically modifying the levels of PPAR? expression and testing their function in vitro; and finally, to dissect the role of PPAR? in vivo by altering its expression level in T cells, EC or both. In the last aim, we will employ our model utilizing a de novo formed vascular bed which allows us to genetically modify EC prior formation of microvascular network. Understanding these cellular mechanisms will have significant impact on treatment of vascular inflammation that is associated with atherosclerosis and graft arteriosclerosis. PUBLIC HEALTH RELEVANCE: This project will determine the role of the transcription factor PPAR? (peroxisome proliferator-activated receptor) transcription factor in a model of vascular diseases such as atherosclerosis. Studies will characterize the interactions and immune activation occurring between human endothelial cells and leukocytes in a novel humanized mouse model. These mechanistic studies will have significant implications for treatment of vascular diseases.