PRECLINICAL STUDIES: CLINICAL RESEARCH
Activation of p38 Mitogen-Activated Protein Kinase Contributes to the Early Cardiodepressant Action of Tumor Necrosis Factor
Mohamed Bellahcene, PhD*,
Sebastien Jacquet, PhD*,
Xue B. Cao, MD*,
Masaya Tanno, MD, PhD*,
Robert S. Haworth, PhD*,
Joanne Layland, PhD ,
Alamgir M. Kabir, MB, BS,
Matthias Gaestel, PhD ,
Roger J. Davis, PhD ,
Richard A. Flavell, PhD||,
Ajay M. Shah, MD, FESC*,
Metin Avkiran, PhD, DSc* and
Michael S. Marber, PhD, FACC*,*
* Cardiovascular Division, King's College London, The Rayne Institute, St. Thomas' Hospital, London, United Kingdom
Cardiovascular Division, King's College London, King's College Hospital, London, United Kingdom
Institute of Biochemistry, Medical School Hannover, Hannover, Germany
Howard Hughes Medical Institute, University of Massachusetts, Worcester, Massachusetts
|| Section of Immunobiology, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, Connecticut
Manuscript received September 2, 2005;
revised manuscript received December 21, 2005,
accepted February 7, 2006.
* Reprint requests and correspondence: Prof. Michael S. Marber, Cardiovascular Division, King's College London, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom (Email: mike.marber{at}kcl.ac.uk).
OBJECTIVES: The purpose of this study was to determine whether p38 mitogen-activated protein kinase (p38-MAPK) contributes to tumor necrosis factor-alpha (TNF )-induced contractile depression.
BACKGROUND: Tumor necrosis factor has both beneficial and detrimental consequences that may result from the activation of different downstream pathways. Tumor necrosis factor activates p38-MAPK, a stress-responsive kinase implicated in contractile depression and cardiac injury.
METHODS: In isolated hearts from mice lacking the p38-MAPK activator, MAPK kinase 3 (MKK3), perfused at constant coronary pressure or flow, we measured the left ventricular developed pressure (LVDP) and the relationship between end-diastolic volume and LVDP in the presence and absence of 10 ng/ml TNF.
RESULTS: Within 15 min at constant pressure, TNF significantly reduced LVDP and coronary flow in outbred and mkk3+/+ mice. This early negative inotropic effect was associated with a marked phosphorylation of both p38-MAPK and its indirect substrate, HSP27. In hearts lacking MKK3, TNF failed to activate p38-MAPK or to cause significant contractile dysfunction. The actions of TNF were similarly attenuated in MAPK-activated protein kinase 2 (MK2)-deficient hearts, which have a marked reduction in myocardial p38-MAPK protein content, and by the p38-MAPK catalytic site inhibitor SB203580 (1 µmol/l). Under conditions of constant coronary flow, the p38-MAPK activation and contractile depression induced by TNF, though attenuated, remained sensitive to the absence of MKK3 or the presence of SB203580. The role of p38-MAPK in TNF-induced contractile depression was confirmed in isolated murine cardiac myocytes exposed to SB203580 or lacking MKK3.
CONCLUSIONS: Tumor necrosis factor activates p38-MAPK in the intact heart and in isolated cardiac myocytes through MKK3. This activation likely contributes to the early cardiodepressant action of TNF.
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Abbreviations and Acronyms
| | LVDP = left ventricular developed pressure | | LVEDP = left ventricular end-diastolic pressure | | MK2 = mitogen-activated protein kinase-activated protein kinase 2 | | MKK3 = mitogen-activated protein kinase-kinase 3 | | p38-MAPK = p38 mitogen-activated protein kinase | | TNF = tumor necrosis factor-alpha |
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