Document Detail


The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy.
MedLine Citation:
PMID:  12122119     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.
Authors:
Junichi Sadoshima; Olivier Montagne; Qian Wang; Guiping Yang; Jill Warden; Jing Liu; Gen Takagi; Vijaya Karoor; Chull Hong; Gary L Johnson; Dorothy E Vatner; Stephen F Vatner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  110     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2002 Jul 
Date Detail:
Created Date:  2002-07-17     Completed Date:  2002-08-14     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  271-9     Citation Subset:  AIM; IM    
Affiliation:
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103, USA. Sadoshju@umdnj.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / physiology
Atrial Natriuretic Factor / genetics
Blood Pressure / physiology*
Enzyme Activation
Gene Expression
Hypertrophy, Left Ventricular / etiology*,  pathology,  physiopathology
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 1*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitogen-Activated Protein Kinases / physiology*
Protein-Serine-Threonine Kinases / deficiency,  genetics,  physiology*
Transforming Growth Factor beta / genetics
Tumor Necrosis Factor-alpha / genetics
Grant Support
ID/Acronym/Agency:
AG-14121/AG/NIA NIH HHS; DK37871/DK/NIDDK NIH HHS; GM-30324/GM/NIGMS NIH HHS; HL-33065/HL/NHLBI NIH HHS; HL-33107/HL/NHLBI NIH HHS; HL-59139/HL/NHLBI NIH HHS; HL-65182/HL/NHLBI NIH HHS; HL-65183/HL/NHLBI NIH HHS; HL-67724/HL/NHLBI NIH HHS; HL-67727/HL/NHLBI NIH HHS; HL-69020/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Transforming Growth Factor beta; 0/Tumor Necrosis Factor-alpha; 85637-73-6/Atrial Natriuretic Factor; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.25/MAP Kinase Kinase Kinase 1; EC 2.7.11.25/Map3k1 protein, mouse
Comments/Corrections

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