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MEK1-induced physiological hypertrophy inhibits chronic post-myocardial infarction remodeling in mice.
MedLine Citation:
PMID:  22821618     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
AIMS: Although activation of MEK-ERK signaling is known to be cardioprotective during acute reperfusion injury, the effect of MEK activation on chronic changes in ventricular structure and function during the more complex process of remodeling after myocardial infarction (MI) with or without reperfusion remains uncertain. METHODS/RESULTS: Four weeks after permanent coronary ligation, LV fractional shorting, preload recruitable stroke work and end-systolic elastance were all preserved in transgenic mice with CM-specific upregulation of the MEK1-ERK1/2 signaling pathway (MEK1Tg) compared to wildtype (WT) controls (5.8% decline vs. 17.3%, P < 0.01; 603 ± 98 mmHg vs. 335 ± 98, P < 0.05; 6.14 ± 0.57 mmHg/µL vs. 3.92 ± 0.60, P< 0.05, respectively). Despite similar initial infarct sizes, post-MI remodeling was significantly reduced in MEK1Tg, demonstrated by reductions in chronic infarct size (28.5 ± 3.1% vs. 47.8 ± 3.2%), myocardial fibrosis (3.98 ± 0.74% vs. 9.27 ± 1.97%) and apoptosis (0.66 ± 0.11% vs. 1.60 ± 0.34%). Higher phosphorylation (i.e. activation) of pro-survival transcription factor STAT3, higher expression of anti-apoptotic protein Bcl2, and higher phosphorylation (i.e. inactivation) of pro-apoptotic BAD were observed in the post-MI remote myocardium of MEK1Tg. MMP2 activity was higher in MEK1Tg, while expression of TIMP3 and MMP9 activity were lower in transgenic mice. CONCLUSION: Beyond any immediate cardioprotective effect, therapeutic activation of MEK1-ERK1/2 signaling during the chronic post-MI period may preserve LV function by increasing the expression of pro-survival factors and by suppressing factors, such as the balance between matrix modulating proteins, that promote pathological remodeling in the remote myocardium. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.
Authors:
Che-Chung Yeh; Deepak Malhotra; Yi-Lin Yang; Yanchun Xu; Yanying Fan; Hongzhe Li; Michael J Mann
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-20
Journal Detail:
Title:  Journal of cellular biochemistry     Volume:  -     ISSN:  1097-4644     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8205768     Medline TA:  J Cell Biochem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Affiliation:
Division of Cardiothoracic Surgery, University of California, San Francisco and VA Medical Center, San Francisco, CA, United States.
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