TY - JOUR
T1 - The role of extracellular signal-related kinase during abdominal aortic aneurysm formation
AU - Ghosh, Abhijit
AU - Dimusto, Paul D.
AU - Ehrlichman, Lauren K.
AU - Sadiq, Omar
AU - McEvoy, Brendan
AU - Futchko, John S.
AU - Henke, Peter K.
AU - Eliason, Jonathan L.
AU - Upchurch, Gilbert R.
N1 - Funding Information:
This work was supported by National Institutes of Health grants R01 HL081629-01 and 3R01 HL081629-03S1 to Dr Upchurch.
PY - 2012/11
Y1 - 2012/11
N2 - 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.
AB - 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.
KW - AAA
KW - ERK
KW - MAPK
KW - MC
KW - MCP-1
KW - ME
KW - MEK
KW - MMP
KW - RANTES
KW - abdominal aortic aneurysm
KW - control mice
KW - extracellular signal-related kinase
KW - male elastase infused mice
KW - matrix-degrading metalloproteinases
KW - mitogen-activated protein kinase
KW - mitogen-activated protein kinase kinase
KW - monocyte chemotactic protein-1
KW - pMEK
KW - phospho-mitogen-activated protein kinase kinase
KW - regulated upon activation, normal T cell expressed, and secreted
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U2 - 10.1016/j.jamcollsurg.2012.06.414
DO - 10.1016/j.jamcollsurg.2012.06.414
M3 - Article
C2 - 22917644
AN - SCOPUS:84867844538
SN - 1072-7515
VL - 215
SP - 668-680.e1
JO - Journal of the American College of Surgeons
JF - Journal of the American College of Surgeons
IS - 5
ER -