OBJECTIVES: The purpose of this study was to determine whether p38
mitogen-activated protein kinase (p38-MAPK) contributes to
tumor necrosis factor-alpha (TNFalpha)-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 TNFalpha. RESULTS: Within 15 min at constant pressure, TNFalpha 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, TNFalpha failed to activate p38-MAPK or to cause significant contractile dysfunction. The actions of TNFalpha 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 micromol/l). Under conditions of constant
coronary flow, the p38-MAPK
activation and contractile depression induced by TNFalpha, though
attenuated, remained sensitive to the absence of
MKK3 or the presence of SB203580. The role of p38-MAPK in TNFalpha-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 TNFalpha.
