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(-/-) mice after arterial wire injury. CONCLUSIONS: The present data suggest that ligand-dependent formation of HMGA1-Ubc9-PPAR? complexes facilitates PPAR? SUMOylation, which results in the prevention of SMRT corepressor clearance and induction of MMP-9 transrepression. These data provide new information on PPAR?-dependent vascular transcriptional regulation and help us to understand the molecular consequences of therapeutic interventions with PPAR? ligands in the vasculature.
High-mobility group A1 protein: a new coregulator of peroxisome proliferator-activated receptor-?-mediated transrepression in the vasculature.
Fusco A;
2012
Abstract
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(-/-) mice after arterial wire injury. CONCLUSIONS: The present data suggest that ligand-dependent formation of HMGA1-Ubc9-PPAR? complexes facilitates PPAR? SUMOylation, which results in the prevention of SMRT corepressor clearance and induction of MMP-9 transrepression. These data provide new information on PPAR?-dependent vascular transcriptional regulation and help us to understand the molecular consequences of therapeutic interventions with PPAR? ligands in the vasculature.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
