期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 8, 页码 3161-3166出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1222051110
关键词
monocyte adhesion; THP-1 cells; inflammatory co-repressor; vascular dysfunction; endothelium
资金
- National Institutes of Health [HL89940, HL93731, HL080518, HL108735]
B-cell lymphoma-6 protein (Bcl-6) is a corepressor for inflammatory mediators such as vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 and -3, which function to recruit monocytes to vascular endothelial cells upon inflammation. Poly [ADP ribose] polymerase 1 (PARP-1) is proinflammatory, in part through its binding at the Bcl-6 intron 1 to suppress Bcl-6 expression. We investigated the mechanisms by which PARP-1 dissociates from the Bcl-6 intron 1, ultimately leading to attenuation of endothelial inflammation. Analysis of the PARP-1 primary sequence suggested that phosphorylation of PARP-1 Serine 177 (Ser-177) by AMP-activated protein kinase (AMPK) is responsible for the induction of Bcl-6. Our results show that AMPK activation with treatment of 5-aminoimi-dazole-4-carboxamide ribonucleotide, metformin, or pulsatile shear stress induces PARP-1 dissociation from the Bcl-6 intron 1, increases Bcl-6 expression, and inhibits expression of inflammatory mediators. Conversely, AMPK alpha suppression or knockdown produces the opposite effects. The results demonstrate an anti-infamatory pathway linking AMPK, PARP-1, and Bcl-6 in endothelial cells.
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