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Department of Cardiology, KCL, The Rayne Institute, St. Thomas’ Hospital London SE1 7EH, U.K.; and
* Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
1Correspondence: Department of Cardiology, KCL, The Rayne Institute, St. Thomas’ Hospital, London SE1 7EH, U.K. E-mail: mike.marber{at}kcl.ac.uk
Activation of protein kinase C (PKC) and more recently mitogen-activated
protein kinases (MAPKs) have been associated with the cardioprotective
effect of ischemic preconditioning. We examined the interplay between
these kinases in a characterized model of ischemic preconditioning in
cultured rat neonatal ventricular cardiocytes where ectopic expression
of active PKC-
results in protection. Two members of the MAPK
family, p38 and p42/44, were activated transiently during
preconditioning by brief simulated ischemia/reoxygenation.
Overexpression of active PKC-, rather than augmenting, completely
abolished this activation. We therefore determined whether a similar
process occurred during lethal prolonged simulated ischemia. In
contrast to ischemia, brief, lethal-simulated ischemia activated only
p38 (2.8±0.45 vs. basal, P<0.01), which was attenuated
by expression of active PKC- or by preconditioning (0.48±0.1 vs.
ischemia, P<0.01). To determine whether reduced p38
activation was the cause or an effect of protection, we used SB203580,
a p38 inhibitor. SB203580 reduced ischemic injury (CK release
38.0±3.1%, LDH release 77.3±4.0%, and MTT bioreduction 127.1±4.8%
of control, n=20, P<0.05). To determine
whether p38 activation was isoform selective, myocytes were infected
with adenoviruses encoding wild-type p38
or p38ß. Transfected
p38 and ß show differential activation (P<0.001)
during sustained simulated ischemia, with p38 remaining activated
(1.48±0.36 vs. basal) but p38ß deactivated (0.36±0.1 vs. basal,
P<0.01). Prior preconditioning prevented the activation
of p38 (0.65±0.11 vs. ischemia, P<0.05). Moreover,
cells expressing a dominant negative p38, which prevented ischemic
p38 activation, were resistant to lethal simulated ischemia (CK release
82.9±3.9% and MTT bioreduction 130.2±6.5% of control,
n=8, P<0.05). Thus, inhibition of p38
activation during ischemia reduces injury and may contribute to
preconditioning-induced cardioprotection in this model.—Saurin,
A. T., Martin, J. L., Heads, R. J., Foley, C.,
Mockridge, J. W., Wright, M. J., Wang, Y., Marber, M. S.
The role of differential activation of p38-mitogen-activated protein
kinase in preconditioned ventricular myocytes.
Key Words: myocardial ischemia • cardioprotection • ischemic preconditioning • cytoprotection
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