[摘要]：Rationale: The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) 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 gamma. Methods and Results: Here, we report a molecular pathway in vascular smooth muscle cells by which ligand-activated PPAR gamma represses transcriptional activation of the matrix-degrading matrix metalloproteinase-9 (MMP-9) gene, a crucial mediator of vascular injury. PPAR gamma-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 gamma and regulation by HMGA1 required PPAR gamma SUMOylation at K367. This process was associated with formation of a complex between PPAR gamma, HMGA1, and the SUMO E2 ligase Ubc9 (ubiquitin-like protein SUMO-1 conjugating enzyme). After PPAR gamma ligand stimulation, HMGA1 and PPAR gamma 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 gamma signaling was underlined by the complete absence of vascular protection through a PPAR gamma ligand in HMGA1(-/-) mice after arterial wire injury. Conclusions: The present data suggest that ligand-dependent formation of HMGA1-Ubc9-PPAR gamma complexes facilitates PPAR gamma SUMOylation, which results in the prevention of SMRT corepressor clearance and induction of MMP-9 transrepression. These data provide new information on PPAR gamma-dependent vascular transcriptional regulation and help us to understand the molecular consequences of therapeutic interventions with PPAR gamma ligands in the vasculature. (Circ Res. 2012;110:394-405.)
