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- Title
AMPK Suppresses Vascular Inflammation In Vivo by Inhibiting Signal Transducer and Activator of Transcription-1.
- Authors
Chaoyong He; Hongliang Li; Viollet, Benoit; Ming-Hui Zou; Zhonglin Xie; He, Chaoyong; Li, Hongliang; Zou, Ming-Hui; Xie, Zhonglin
- Abstract
Activation of AMPK suppresses inflammation, but the underlying mechanisms remain poorly understood. This study was designed to characterize the molecular mechanisms by which AMPK suppresses vascular inflammation. In cultured human aortic smooth muscle cells, pharmacologic or genetic activation of AMPK inhibited the signal transducer and activator of transcription-1 (STAT1), while inhibition of AMPK had opposite effects. Deletion of AMPKα1 or AMPKα2 resulted in activation of STAT1 and in increases in proinflammatory mediators, both of which were attenuated by administration of STAT1 small interfering RNA or fludarabine, a selective STAT1 inhibitor. Moreover, AMPK activation attenuated the proinflammatory actions induced by STAT1 activators such as interferon-γ and angiotensin II (AngII). Mechanistically, we found that AMPK activation increased, whereas AMPK inhibition decreased, the levels of mitogen-activated protein kinase phosphatase-1 (MKP-1), an inducible nuclear phosphatase, by regulating proteasome-dependent degradation of MKP-1. Gene silencing of MKP-1 increased STAT1 phosphorylation and prevented 5-aminoimidazole-4-carboxyamide ribonucleoside-reduced STAT1 phosphorylation. Finally, we found that infusion of AngII caused a more severe inflammatory response in AMPKα2 knockout mouse aortas, all of which were suppressed by chronic administration of fludarabine. We conclude that AMPK activation suppresses STAT1 signaling and inhibits vascular inflammation through the upregulation of MKP-1.
- Subjects
VASCULITIS; CELLULAR signal transduction; TRANSCRIPTION factors; SMOOTH muscle; FLUDARABINE; SMALL interfering RNA; ANGIOTENSIN II; PROTEASOMES; ANIMAL experimentation; BIOCHEMISTRY; CARRIER proteins; CELL culture; GENES; INTERFERONS; PHENOMENOLOGY; MICE; NONSTEROIDAL anti-inflammatory agents; PHOSPHATASES; PHOSPHORYLATION; PHOSPHOTRANSFERASES; PROTEINS; RECOMBINANT proteins; RESEARCH funding; STATISTICAL sampling; THORACIC aorta; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
Diabetes, 2015, Vol 64, Issue 12, p4285
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db15-0107