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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."xsd:string
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http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/author"Ghosh A."xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/author"McEvoy B."xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/author"Eliason J.L."xsd:string
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http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/author"Henke P.K."xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/author"Upchurch G.R. Jr."xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/author"DiMusto P.D."xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/author"Ehrlichman L.K."xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/author"Futchko J.S."xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/date"2012"xsd:gYear
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/name"J Am Coll Surg"xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/pages"668-680.e1"xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/title"The role of extracellular signal-related kinase during abdominal aortic aneurysm formation."xsd:string
http://purl.uniprot.org/citations/22917644http://purl.uniprot.org/core/volume"215"xsd:string
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