RAGE signaling mediates post-injury arterial neointima formation by suppression of liver kinase B1 and AMPK activity

Atherosclerosis. 2012 Jun;222(2):417-25. doi: 10.1016/j.atherosclerosis.2012.04.001. Epub 2012 Apr 11.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Carotid Arteries / metabolism
  • Carotid Arteries / pathology
  • Carotid Artery Injuries / enzymology*
  • Carotid Artery Injuries / genetics
  • Carotid Artery Injuries / pathology
  • Cattle
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Down-Regulation
  • Enzyme Activation
  • Gene Knockdown Techniques
  • Ligands
  • Liver / enzymology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Neointima
  • Phosphorylation
  • Protein Phosphatase 2 / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • S100 Proteins / metabolism
  • STAT3 Transcription Factor / metabolism
  • Serum Albumin / metabolism
  • Signal Transduction

Substances

  • Ligands
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • S100 Proteins
  • STAT3 Transcription Factor
  • Serum Albumin
  • Stat3 protein, mouse
  • glycated serum albumin
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Protein Phosphatase 2