High-mobility group A1 protein: a new coregulator of peroxisome proliferator-activated receptor-γ-mediated transrepression in the vasculature.
BACKGROUND
The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ.


RESULTS
Here, we report a molecular pathway in vascular smooth muscle cells by which ligand-activated PPARγ represses transcriptional activation of the matrix-degrading matrix metalloproteinase-9 (MMP-9) gene, a crucial mediator of vascular injury. PPARγ-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 PPARγ and regulation by HMGA1 required PPARγ SUMOylation at K367. This process was associated with formation of a complex between PPARγ, HMGA1, and the SUMO E2 ligase Ubc9 (ubiquitin-like protein SUMO-1 conjugating enzyme). After PPARγ ligand stimulation, HMGA1 and PPARγ 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 PPARγ signaling was underlined by the complete absence of vascular protection through a PPARγ ligand in HMGA1(-/-) mice after arterial wire injury.


CONCLUSIONS
The present data suggest that ligand-dependent formation of HMGA1-Ubc9-PPARγ complexes facilitates PPARγ SUMOylation, which results in the prevention of SMRT corepressor clearance and induction of MMP-9 transrepression. These data provide new information on PPARγ-dependent vascular transcriptional regulation and help us to understand the molecular consequences of therapeutic interventions with PPARγ ligands in the vasculature.
Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Germany.
Mandy
M
Bloch
André
A
Prock
Francesco
F
Paonessa
Verena
V
Benz
Ilse N
IN
Bähr
Lena
L
Herbst
Henning
H
Witt
Kai
K
Kappert
Joachim
J
Spranger
Philipp
P
Stawowy
Thomas
T
Unger
Alfredo
A
Fusco
Daniel
D
Sedding
Antonio
A
Brunetti
Anna
A
Foryst-Ludwig
Ulrich
U
Kintscher
D000818:Animals; D019332:Endothelin-1 / Q000378:metabolism; D005263:Femoral Artery / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D025741:HMGA1a Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D019332:Endothelin-1; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D025741:HMGA1a Protein; D044763:Ubiquitin-Conjugating Enzymes; D020780:Matrix Metalloproteinase 9; D000098843:Ubiquitin-Conjugating Enzyme UBC9