Mocanu MM, Baxter GF, Yue Y, Critz SD, Yellon DM: The p38 MAPK inhibitor, SB203580, abrogates ischaemic preconditioning in rat heart but timing of administration is critical. Basic Res Cardiol 95: 472-8
There is debate concerning the involvement of p38 mitogen activated protein kinase (MAPK) in the mediation of ischaemic preconditioning. Pharmacological inhibition of p38 MAPK with SB203580 has been reported to block preconditioning in some studies but not in others. We hypothesised that this divergence could be due to differences in the timing of inhibitor administration. Isolated rat hearts were perfused in the Langendorff mode and subjected to 35 min regional ischaemia followed by 120 min reperfusion. Hearts were then double stained with Evans' blue and triphenyltetrazolium chloride to determine risk (R) and infarct zones (I), expressed as I/R% ratios. Preconditioned hearts were subjected to 2 times 5 min global ischaemia with 10 min intervening reperfusion. SB203580 10 microM was perfused either during the preconditioning protocol (PC+/-SB-early),just prior to and during the first 15 min of the lethal ischaemia (PC+/-SB-late) or prior to regional ischaemia in the absence of preconditioning. Ischaemic preconditioning significantly limited infarct size (I/R 38.9 +/- 3.0% in control vs 13.4 +/- 2.4%, P < 0.01). In the PC+/-SB-early group, preconditioning was still fully protective (I/R% 14.6 +/- 1.0). However, in the PC+/-SB-late group, SB203580 completely blocked the protection afforded by preconditioning (I/R% 33.6 +/- 4.4%, P < 0.01 vs 13.4 +/- 2.4% in preconditioned hearts, p < 0.05). SB203580 alone did not affect infarct size when given prior to and during regional ischaemia (I/R 36.2 +/- 2.7%). These histological data are corroborated by a significant increase in p38 MAPK activation in the preconditioned hearts during sustained ischaemia in comparison with the controls. In conclusion the activation of p38 MAPK during lethal ischaemia, but not during the ischaemic preconditioning protocol, is essential for the mediation of protection and may resolve some of the earlier controversy surrounding the use of SB203580 in preconditioning studies.
"Those groups that support stimulation of PKC activity by reactive oxygen species attribute the latter to a modification of the kinase regulatory domain (Cohen et al., 1996) or to activation by phospholipases C and D (Harada et al., 2004). Overall, the observed dissociation between the infarct size and PKC activity in the nicorandil treated group after multiple cycles of preconditioning, may be attributed to the fact that nicorandil increases the levels of reactive oxygen species generated by mitochondria which in fact subsequently mediate protection via at least one tyrosine kinase (Baines et al., 1998) with a p38-MAPK potential key role still remaining under dispute (Mackay and Mochly-Rosen, 1999; Mocanu et al., 2000). Indeed, the role of MAPKs in the signal transduction of preconditioning has been addressed in several studies but the reported data are not conclusive (Hausenloy et al., 2005; Iliodromitis et al., 2002; Nakano et al., 2000a; Sato et al., 2000a; Yue et al., 2002). "
[Show abstract][Hide abstract] ABSTRACT: Nicorandil, a selective mitochondrial K(ATP) channel opener, reinstates the waned protection after multiple cycles of preconditioning. In this study, we determined the signal transduction activated in heart after 3 or 8 cycles of preconditioning and prolonged ischemia in rabbits treated with placebo or nicorandil. In a first series (eight groups) we evaluated the (%) infarct to risk ratio after 30 min ischemia/3 h reperfusion and in a second series (six groups), we assessed the intracellular levels of cyclic GMP (c-GMP), protein kinase C (PKC) activity and p38-mitogen activated protein kinase (p38-MAPK) phosphorylation from heart samples taken during the long ischemia. Cardioprotection by 3 cycles of preconditioning (11.7+/-3.8% vs 45.9+/-5.2% in the control, P<0.001) was lost after 8 cycles (43.9+/-5.1%, P=NS vs control). Nicorandil restored it to the levels of classic preconditioning (13.7+/-2.4% vs 40.8+/-3.5% in respective controls, P<0.001). This was reversed by the p38-MAPK inhibitor SB203580 (48.8+/-5.1%) which had no protective effect in the control group (44.6+/-5.8%). In the placebo-treated rabbits, intracellular c-GMP and PKC were increased only in the group subjected to 3 cycles of preconditioning. Despite that nicorandil equalizes the intracellular levels of c-GMP, PKC and activated p38-MAPK at the long ischemia, specific alterations of p38-MAPK phosphorylation differentiate the protected groups. Our data delineate the signal transduction mechanism mediating the beneficial effect of nicorandil and imply that the recapture of the lost protection is due to a dynamic process of the intracellular mediators accompanied by an increase in p38-MAPK phosphorylation and not to an instantaneous event.
European Journal of Pharmacology 01/2008; 579(1-3):289-97. DOI:10.1016/j.ejphar.2007.10.026 · 2.53 Impact Factor
"The role of p38-MAPK cascade in cardioprotection is also controversial. In isolated rabbit cardiomyocytes (Weinbrenner et al. 1997; Armstrong et al. 2000), rabbit and rat hearts (Maulik et al. 1998; Mocanu et al. 2000; Nakano et al. 2000b), it was shown that inhibition of p38-MAPK by SB 203580 completely abolished protection conferred by IP and a positive role of p38-MAPK in preconditioning was suggested. In accord, Nagarkatti and Sha'fi (1998) also found that protective effect of preconditioning was attenuated in the presence of SB 203580, but not in the presence of PD 98059 in rat myoblast cells). "
[Show abstract][Hide abstract] ABSTRACT: Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes connecting cell-surface receptors to critical regulatory targets within cells. The three major MAPK cascades are known, the extracellular signal-regulated protein kinase (ERK) cascade, c-Jun amino-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) cascade and p38-MAPK cascade. This paper is focused on characterization of these MAPK cascades in terms of their distribution and biological role in some pathological processes (apoptosis, hypertrophy) with a special orientation on the role of MAPKs in cardiovascular system during ischemia/reperfusion.
General Physiology and Biophysics 10/2002; 21(3):231-55. · 1.17 Impact Factor
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