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AMPKα2 exerts its anti-inflammatory effects through PARP-1 and Bcl-6

Brendan Gongol1, Traci Marin, I-Chen Peng

  • 1Biochemistry and Molecular Biology Graduate Program, and Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 6, 2013
PubMed

Insights

AMP-activated protein kinase (AMPK) activation triggers the dissociation of Poly [ADP ribose] polymerase 1 (PARP-1) from the Bcl-6 intron 1. This process enhances B-cell lymphoma-6 protein (Bcl-6) expression, reducing endothelial inflammation.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cardiovascular Research

Background:

  • B-cell lymphoma-6 protein (Bcl-6) acts as a corepressor for inflammatory mediators involved in monocyte recruitment.
  • Poly [ADP ribose] polymerase 1 (PARP-1) promotes inflammation by suppressing Bcl-6 expression through binding to its intron 1.

Purpose of the Study:

  • To investigate the mechanism by which Poly [ADP ribose] polymerase 1 (PARP-1) dissociates from the Bcl-6 intron 1.
  • To elucidate the role of AMP-activated protein kinase (AMPK) in regulating this dissociation and its impact on endothelial inflammation.

Main Methods:

  • Analysis of Poly [ADP ribose] polymerase 1 (PARP-1) primary sequence to identify potential phosphorylation sites.
  • Treatment with AMP-activated protein kinase (AMPK) activators (5-aminoimidazole-4-carboxamide ribonucleotide, metformin, pulsatile shear stress) and inhibitors.
  • Assessment of Poly [ADP ribose] polymerase 1 (PARP-1) binding to Bcl-6 intron 1, Bcl-6 expression, and inflammatory mediator expression.

Main Results:

  • AMPK activation by various stimuli promotes the dissociation of Poly [ADP ribose] polymerase 1 (PARP-1) from the Bcl-6 intron 1.
  • This dissociation leads to increased B-cell lymphoma-6 protein (Bcl-6) expression.
  • AMPK activation and subsequent Bcl-6 upregulation inhibit the expression of key inflammatory mediators, reducing endothelial inflammation.

Conclusions:

  • AMP-activated protein kinase (AMPK) phosphorylation of Poly [ADP ribose] polymerase 1 (PARP-1) at Serine 177 is crucial for its dissociation from the Bcl-6 intron 1.
  • A novel anti-inflammatory pathway involving AMPK, PARP-1, and Bcl-6 in endothelial cells has been identified.
  • Targeting this pathway holds potential for therapeutic interventions in inflammatory conditions.

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