|RAGE signaling mediates post-injury arterial neointima formation by suppression of liver kinase B1 and AMPK activity.|
|PMID: 22552116 Owner: NLM Status: MEDLINE|
|OBJECTIVE: Intima formation involves smooth muscle cell (SMC) proliferation and migration that ultimately drives arterial stenosis, thrombosis, and ischemia in atherosclerosis, hypertension, and arterial revascularization. Receptor for advanced glycation endproducts (RAGE) is a transmembrane signaling receptor implicated in diabetic renal and vascular complications, and post-injury intima formation, partly via Signal transducer and activator of transcription 3 (STAT3) activation. The metabolic super-regulator Adenosine monophosphate kinase (AMPK) inhibits SMC proliferation and intima formation. AMPK activation is promoted by liver kinase B1 (LKB1), and LKB1 inhibits STAT3 activation. Here, we tested the hypothesis that RAGE promotes arterial intima formation by modulating both LKB1 and AMPK.
METHODS AND RESULTS: RAGE ligands (the calgranulin S100A11, and glycated albumin) suppressed AMPK activation in conjunction with increased proliferation and migration of cultured SMCs. These effects were inhibited both by RAGE deficiency and by prior AMPK activation. In SMCs, RAGE ligands decreased LKB1 activity. Moreover, knockdown of both LKB1 and AMPK were associated with increased STAT3 phosphorylation levels. In response to murine carotid artery ligation, expression of RAGE and S100A11 increased, whereas AMPK and LKB1 activity decreased in situ. Conversely, LKB1 and AMPK activity increased in situ, and neointima formation was attenuated in Rage(-/-) mice.
CONCLUSION: The linkage of decreased LKB1 and AMPK activity with increased STAT3 in SMCs mediates the capacity of RAGE ligand-induced signaling to promote neointima formation in response to arterial injury.
|Weifang Yu; Ru Liu-Bryan; Stephanie Stevens; Jagadeesha K Damanahalli; Robert Terkeltaub|
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|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-04-11|
|Title: Atherosclerosis Volume: 222 ISSN: 1879-1484 ISO Abbreviation: Atherosclerosis Publication Date: 2012 Jun|
|Created Date: 2012-05-28 Completed Date: 2012-09-20 Revised Date: 2014-04-08|
Medline Journal Info:
|Nlm Unique ID: 0242543 Medline TA: Atherosclerosis Country: Ireland|
|Languages: eng Pagination: 417-25 Citation Subset: IM|
|Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.|
|APA/MLA Format Download EndNote Download BibTex|
AMP-Activated Protein Kinases
Carotid Arteries / metabolism, pathology
Carotid Artery Injuries / enzymology*, genetics, pathology
Disease Models, Animal
Gene Knockdown Techniques
Liver / enzymology*
Mice, Inbred C57BL
Muscle, Smooth, Vascular / metabolism*, pathology
Protein Phosphatase 2 / metabolism
Protein-Serine-Threonine Kinases / genetics, metabolism*
Receptors, Immunologic / deficiency, genetics, metabolism*
S100 Proteins / metabolism
STAT3 Transcription Factor / metabolism
Serum Albumin / metabolism
|AR1067966/AR/NIAMS NIH HHS; HL077360/HL/NHLBI NIH HHS; HL087252/HL/NHLBI NIH HHS; R01 HL077360/HL/NHLBI NIH HHS; R01 HL087252/HL/NHLBI NIH HHS|
|0/Ligands; 0/Receptors, Immunologic; 0/S100 Proteins; 0/STAT3 Transcription Factor; 0/Serum Albumin; 0/Stat3 protein, mouse; 0/advanced glycosylation end-product receptor; 0/glycosylated serum albumin; EC 2.7.1.-/Stk11 protein, mouse; EC 188.8.131.52/AMP-Activated Protein Kinases; EC 184.108.40.206/Protein-Serine-Threonine Kinases; EC 220.127.116.11/Protein Phosphatase 2|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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