Document Detail


Constitutively active MEK1 rescues cardiac dysfunction caused by overexpressed GSK-3α during aging and hemodynamic pressure overload.
MedLine Citation:
PMID:  22904158     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Expression of GSK-3α is increased in aging hearts and those subjected to hemodynamic overload. Overexpressed GSK-3α inhibits ERK and enhances pressure overload (PO)-induced cardiac dysfunction. We studied whether suppression of the MEK1/ERK pathway contributes to cardiac responses induced by overexpressed GSK-3α using constitutively active MEK1 (CA-MEK1)/GSK-3α bigenic mice (bigenic mice), which were obtained by crossing cardiac-specific GSK-3α transgenic mice (Tg-GSK) and cardiac-specific CA-MEK1 transgenic mice (Tg-MEK1). The suppression of ERK phosphorylation observed in Tg-GSK was eliminated in bigenic mice. At 12 mo, left ventricular (LV) weight/tibia length, LV weight/body weight, and cardiac myocyte size were significantly smaller in Tg-GSK than in nontransgenic mice (NTg), but were not significantly different between Tg-MEK1 and bigenic mice. The LV ejection fraction (LVEF), fractional shortening (FS), and change in pressure over time were significantly lower in Tg-GSK than in NTg, but were not significantly different between bigenic mice and Tg-MEK1. The increase in apoptosis in Tg-GSK was abolished in bigenic mice, although the increase in fibrosis was not. After PO, the decrease in cardiac hypertrophy and the enhancement of apoptosis seen in Tg-GSK were abrogated in bigenic mice. After PO, the LVEF and FS were significantly reduced in Tg-GSK compared with its sham, but not in NTg, Tg-MEK1, or bigenic mice compared with their respective shams. There was no significant difference in LVEF and FS between bigenic mice and Tg-MEK1 after PO. In conclusion, inhibition of the MEK1/ERK pathway mediates the hypertrophy suppression and cardiac dysfunction caused by GSK-3α overexpression in cardiac myocytes.
Authors:
Yasuhiro Maejima; Jonathan Galeotti; Jeffery D Molkentin; Junichi Sadoshima; Peiyong Zhai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-17
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  303     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-16     Completed Date:  2012-12-26     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H979-88     Citation Subset:  IM    
Affiliation:
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry, New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA.
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MeSH Terms
Descriptor/Qualifier:
Aging / physiology*
Animals
Apoptosis / physiology
Cardiomegaly / metabolism*,  pathology,  physiopathology
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Glycogen Synthase Kinase 3 / genetics,  metabolism*
Hemodynamics / physiology
MAP Kinase Kinase 1 / genetics,  metabolism*
MAP Kinase Signaling System / drug effects,  physiology*
Mice
Mice, Transgenic
Myocytes, Cardiac / enzymology,  pathology
Signal Transduction / physiology
Stroke Volume / physiology
Ventricular Dysfunction, Left / metabolism,  pathology,  physiopathology
Ventricular Pressure / physiology
Grant Support
ID/Acronym/Agency:
R01 AG023039/AG/NIA NIH HHS; R01 HL067724/HL/NHLBI NIH HHS; R01 HL091469/HL/NHLBI NIH HHS; R01 HL102738/HL/NHLBI NIH HHS; R01 HL112330/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; EC 2.7.1.-/Map2k1 protein, mouse; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 2.7.11.26/glycogen synthase kinase 3 alpha; EC 2.7.12.2/MAP Kinase Kinase 1
Comments/Corrections

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