AMP-Activated Protein Kinase Suppresses Endothelial Cell Inflammation Through Phosphorylation of Transcriptional Coactivator p300

Abstract

Objective-Considerable evidence supports the early involvement of monocyte/macrophage recruitment to activated endothelial cells by leukocyte adhesion molecules during atherogenesis. AMP-activated protein kinase (AMPK) is highly expressed in vascular endothelial cells, but its impact on monocyte adhesion and the related mechanisms are not fully understood. The present study was designed to evaluate the impact of and gain mechanistic insight into the signaling coupling AMPK function to the antiinflammatory response. Methods and Results-5-Aminoimidazole-4-carboxamide-1-␤-D-ribonucleotide (AICAR) treatment or overexpression of constitutively active AMPK markedly reduced human monocytic human acute monocytic leukemia cell line-1 cell adhesion and the expression of vascular cell adhesion molecule-1 in tumor necrosis factor-␣-activated human aortic endothelial cells. Furthermore, AICAR or constitutively active AMPK overexpression strongly inhibited the histone acetyltransferase activity of the transcriptional coactivator p300 by phosphorylation of Ser89, which in turn decreased tumor necrosis factor-␣-activated p300-mediated acetylation of nuclear factor-B p65 on Lys221 and reduced the DNA binding activity of nuclear factor-B by inhibiting its recruitment to its target gene promoters. AMPK phosphorylates the transcriptional coactivator p300 via the atypical protein kinase C/. Conclusion-Our findings demonstrate that transcriptional coactivator p300 phosphorylation at Ser89 by AMPK is critical for the therapeutic effect of AMPK and may be a potential target for pharmaceutical intervention in inflammatory diseases such as atherosclerosis. (Arterioscler Thromb Vasc Biol. 2011;31:2897-2908.)

AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

“…The delayed recruitment of STAT6 to the ALOX15 promoter may be associated with histone and STAT6 acetylation by p300. Interestingly, AMPK has been reported to inhibit p300 activity (34). Although we failed to detect STAT6 acetylation in our system (data not shown), reduced histone acetylation at the ALOX15 promoter conformed with this mechanism.…”

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

“…Further, AICAR administration provides anti-inflammatory effects in vascular cells in vitro and in vivo (6,9,40). The nonuniform distribution of atheroma in the arterial tree underscores the importance of the local flow patterns in inflammation.…”

“…For example, clinical trials using anti-TNF-α monoclonal antibodies (mAbs) to treat various inflammatory diseases not only alleviates the targeted diseases but also improves vascular function (4,5). AMP-activated protein kinase (AMPK), which is activated under various environmental and metabolic stresses, exerts anti-inflammatory effects on vasculature, in part through inhibition of chemoattractants and adhesion molecules by regulating STAT3, NF-κB, and p300 pathways (6)(7)(8)(9).…”

A Cell-Autonomous Molecular Cascade Initiated by AMP-Activated Protein Kinase Represses Steroidogenesis

“…AMPK is known to reduce p300 recruitment to its target promoter (38,39). Since p300 is required for Nr4a1 transcription in other cells (40,41), ChIP assays were performed to test whether activated AMPK impairs p300 recruitment on the Nr4a1 promoter.…”