http://www.cnr.it/ontology/cnr/individuo/prodotto/ID206830
High-mobility group A1 protein: a new coregulator of peroxisome proliferator-activated receptor-?-mediated transrepression in the vasculature. (Articolo in rivista)
- Type
- Label
- High-mobility group A1 protein: a new coregulator of peroxisome proliferator-activated receptor-?-mediated transrepression in the vasculature. (Articolo in rivista) (literal)
- Anno
- 2012-01-01T00:00:00+01:00 (literal)
- Alternative label
Bloch M, Prock A, Paonessa F, Benz V, Bähr IN, Herbst L, Witt H, Kappert K, Spranger J, Stawowy P, Unger T, Fusco A, Sedding D, Brunetti A, Foryst-Ludwig A, Kintscher U. (2012)
High-mobility group A1 protein: a new coregulator of peroxisome proliferator-activated receptor-?-mediated transrepression in the vasculature.
in Circulation research
(literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- Bloch M, Prock A, Paonessa F, Benz V, Bähr IN, Herbst L, Witt H, Kappert K, Spranger J, Stawowy P, Unger T, Fusco A, Sedding D, Brunetti A, Foryst-Ludwig A, Kintscher U. (literal)
- Rivista
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
- Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Germany.
Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy. (literal)
- Titolo
- High-mobility group A1 protein: a new coregulator of peroxisome proliferator-activated receptor-?-mediated transrepression in the vasculature. (literal)
- 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. (literal)
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