Original Research High-Mobility Group A1 Protein A New Coregulator of Peroxisome Proliferator–Activated Receptor-–Mediated Transrepression in the Vasculature

Rationale: The nuclear receptor peroxisome proliferator–activated receptor- (PPAR) is an important regulator of gene transcription in vascular cells and mediates the vascular protection observed with antidiabetic glitazones. Objective: To determine the molecular mechanism of ligand-dependent transrepression in vascular smooth muscle cells and their impact on the vascular protective actions of PPAR. Methods and Results: Here, we report a molecular pathway in vascular smooth muscle cells by which ligand-activated PPAR represses transcriptional activation of the matrix-degrading matrix metalloproteinase-9 (MMP-9) gene, a crucial mediator of vascular injury. PPAR-mediated transrepression of the MMP-9 gene was dependent on the presence of the high-mobility group A1 (HMGA1) protein, a gene highly expressed in vascular smooth muscle cells, newly identified by oligonucleotide array expression analysis. Transrepression of MMP-9 by PPAR and regulation by HMGA1 required PPAR SUMOylation at K367. This process was associated with formation of a complex between PPAR, HMGA1, and the SUMO E2 ligase Ubc9 (ubiquitin-like protein SUMO-1 conjugating enzyme). After PPAR ligand stimulation, HMGA1 and PPAR were recruited to the MMP-9 promoter, which facilitated binding of SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), a nuclear corepressor involved in transrepression. The relevance of HMGA1 for vascular PPAR signaling was underlined by the complete absence of vascular protection through a PPAR ligand in HMGA1