| First Author | Bloch M | Year | 2012 |
| Journal | Circ Res | Volume | 110 |
| Issue | 3 | Pages | 394-405 |
| PubMed ID | 22207709 | Mgi Jnum | J:192701 |
| Mgi Id | MGI:5466225 | Doi | 10.1161/CIRCRESAHA.111.253658 |
| Citation | Bloch M, et al. (2012) High-mobility group A1 protein: a new coregulator of peroxisome proliferator-activated receptor-gamma-mediated transrepression in the vasculature. Circ Res 110(3):394-405 |
| abstractText | RATIONALE: The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma. METHODS AND RESULTS: Here, we report a molecular pathway in vascular smooth muscle cells by which ligand-activated PPARgamma represses transcriptional activation of the matrix-degrading matrix metalloproteinase-9 (MMP-9) gene, a crucial mediator of vascular injury. PPARgamma-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 PPARgamma and regulation by HMGA1 required PPARgamma SUMOylation at K367. This process was associated with formation of a complex between PPARgamma, HMGA1, and the SUMO E2 ligase Ubc9 (ubiquitin-like protein SUMO-1 conjugating enzyme). After PPARgamma ligand stimulation, HMGA1 and PPARgamma 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 PPARgamma signaling was underlined by the complete absence of vascular protection through a PPARgamma ligand in HMGA1(-/-) mice after arterial wire injury. CONCLUSIONS: The present data suggest that ligand-dependent formation of HMGA1-Ubc9-PPARgamma complexes facilitates PPARgamma SUMOylation, which results in the prevention of SMRT corepressor clearance and induction of MMP-9 transrepression. These data provide new information on PPARgamma-dependent vascular transcriptional regulation and help us to understand the molecular consequences of therapeutic interventions with PPARgamma ligands in the vasculature. |
