| The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy. | |
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MedLine Citation:
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PMID: 12122119 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 110 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 2002 Jul |
Date Detail:
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Created Date: 2002-07-17 Completed Date: 2002-08-14 Revised Date: 2013-04-18 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 271-9 Citation Subset: AIM; IM |
Affiliation:
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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 |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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:
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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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