The Role of Extracellular Signal-Related Kinase During Abdominal Aortic Aneurysm Formation

J Am Coll Surg. 2012 Nov;215(5):668-680.e1. doi: 10.1016/j.jamcollsurg.2012.06.414. Epub 2012 Aug 21.

Abstract

Background: It is hypothesized that activation of extracellular signal-related kinase (ERK) is critical in activating matrix metalloproteinases (MMPs) during abdominal aortic aneurysm (AAA) formation.

Study design: C57BL/6 male mice underwent either elastase or heat-inactivated elastase aortic perfusion (n = 9 per group). Mouse aortic smooth muscle cells were transfected with ERK-1 and 2 siRNA along with or without elastase treatment. Mouse and human aortic tissue were analyzed by Western blots, zymograms, and immunohistochemistry, and statistical analysis was done using Graphpad and Image J softwares.

Results: Western blot and immunohistochemistry documented increased phospho-mitogen-activated protein kinase kinase-1/2 (pMEK-1/2; 153%, p = 0.270 by Western) and pERK (171%, p = 0.004 by Western blot) in the elastase perfused aortas. Male ERK-1(-/-) mice underwent elastase perfusion, and aortic diameter was determined at day 14. ERK-1(-/-) mice failed to develop AAA, and histologic analysis depicted intact collagen and elastin fibers in the aortas. Zymography of aortas of elastase-treated ERK-1(-/-) mice showed lower levels of proMMP2 (p < 0.005) and active MMP2 (p < 0.0001), as well as proMMP9 (p = 0.037) compared with C57BL/6 mice. siRNA transfection of ERK-1 and -2 significantly reduced formation of pro- and active MMP2 (p < 0.01 for both isoforms) in aortic smooth muscle cells treated with elastase in vitro. Human AAA tissue had significantly elevated levels of pMEK-1/2 (150%, p = 0.014) and pERK (159%, p = 0.013) compared with control tissues.

Conclusions: The MAPK (mitogen-activated protein kinase)/ERK pathway is an important modulator of MMPs during AAA formation. Targeting the ERK pathway by reagents that inhibit either the expression or phosphorylation of ERK isoforms could be a potential therapy to prevent AAA formation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aorta, Abdominal / metabolism*
  • Aortic Aneurysm, Abdominal / etiology
  • Aortic Aneurysm, Abdominal / metabolism*
  • Biomarkers / metabolism
  • Blotting, Western
  • Cells, Cultured
  • Enzyme Precursors / metabolism
  • Gelatinases / metabolism
  • Humans
  • Immunohistochemistry
  • MAP Kinase Signaling System / physiology*
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Transfection

Substances

  • Biomarkers
  • Enzyme Precursors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Gelatinases
  • pro-matrix metalloproteinase 9
  • progelatinase
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse