Key Words: peroxisome proliferator-activated receptor Ⅲ atherosclerosis Ⅲ diabetes mellitus Ⅲ vascular biology T he peroxisome proliferator-activated receptor ␥ (PPAR␥) belongs to the nuclear receptor family of ligand-dependent transcription factors. 1 PPAR␥ plays an important role in glucose homeostasis and is pharmacologically targeted by the class of insulin-sensitizing drugs named thiazolidinediones or glitazones. 1,2 In addition to its critical metabolic function, glitazone-activated PPAR␥ exhibits potent anti-inflammatory and vascular protective effects by directly affecting gene expression in monocytes/macrophages, T lymphocytes, endothelial cells, and vascular smooth muscle cells (VSMCs). 3,4 PPAR␥-mediated gene regulation comprises several distinct mechanisms, including ligand-dependent transactivation, ligand-independent repression, and ligand-dependent transrepression. 4 For its anti-inflammatory actions in macrophages, inhibition of gene expression by ligand-dependent transrepression has been identified as a key molecular process. 5 However, the molecular mechanisms underlying Original received July 26, 2011; revision received December 14, 2011; accepted December 16, 2011. In November 2011, the average time from submission to first decision for all original research papers submitted to Circulation Research was 15 days.From the Center for Cardiovascular Research, Institute of Pharmacology, Campus Charité Mitte (M.B., V.B., I.N.B., L.H., H.W., K.K., T.U., A.F.-L., U.K.), and Department of Endocrinology, Diabetes, and Nutrition (J.S.), Charité Universitätsmedizin Berlin, Berlin, Germany; Department of Cardiology, Giessen University (A.P., D.S.), Giessen, Germany; Department of Clinical and Experimental Medicine G. Salvatore, University of Catanzaro Magna Graecia (F.P., A.B.), Catanzaro, Italy; German Heart Institute Berlin, Department of Cardiology (P.S.), Berlin, Germany; and Instituto di Endocrinologia ed Oncologia Sperimentale del CNR Gaetano Salvatore, Università di Napoli Federico II (A.F.), Napoli, Italy.* Matrix metalloproteinase-9 (MMP-9) and endothelin-1 (ET-1) are PPAR␥ target genes in vascular cells involved in the development of atherosclerosis and have been characterized as important mediators of the vascular protective actions of PPAR␥. 6 -8 PPAR␥ activation by glitazones results in marked inhibition of MMP-9 mRNA/protein expression and its gelatinolytic activity in VSMCs, which indicates MMP-9 as a potential candidate gene for ligand-dependent transrepression in these cells. 8 High-mobility group (HMG) proteins are chromatinbinding proteins that consist of the 3 family members HMGA, HMGB, and HMGN. 9 HMG proteins act as architectural elements that affect various DNA-dependent processes in the context of chromatin. 9 Via DNA-protein or protein-protein interactions, HMG proteins regulate gene transcription and influence multiple biological processes, including cell growth, proliferation, differentiation, and death. 9 The present study aimed to characterize the molecular process of ligand-de...