The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes

Adrian T. Saurin, Jody L. Martin, Richard J. Heads, Claire Foley, James W. Mockridge, Matt J. Wright, Yibin Wang, Michael S. Marber

Research output: Contribution to journalArticle

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Abstract

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-δ 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-δ, 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-δ 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 p38α or p38β. Transfected p38α and β show differential activation (P<0.001) during sustained simulated ischemia, with p38α remaining activated (1.48±0.36 vs. basal) but p38β deactivated (0.36±0.1 vs. basal, P<0.01). Prior preconditioning prevented the activation of p38α (0.65±0.11 vs. ischemia, P<0.05). Moreover, cells expressing a dominant negative p38α, 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 p38α activation during ischemia reduces injury and may contribute to preconditioning-induced cardioprotection in this model.

Original languageEnglish
Pages (from-to)2237-2246
Number of pages10
JournalFASEB Journal
Volume14
Issue number14
Publication statusPublished - 1 Nov 2000

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p38 Mitogen-Activated Protein Kinases
Muscle Cells
Ischemia
Chemical activation
Protein Kinase C
Ischemic Preconditioning
Mitogen-Activated Protein Kinases
Wounds and Injuries
Rats
Adenoviridae
Protein Isoforms
Phosphotransferases
Cells

Keywords

  • Cardioprotection
  • Cytoprotection
  • Ischemic preconditioning
  • Myocardial ischemia

Cite this

Saurin, A. T., Martin, J. L., Heads, R. J., Foley, C., Mockridge, J. W., Wright, M. J., ... Marber, M. S. (2000). The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. FASEB Journal, 14(14), 2237-2246.
Saurin, Adrian T. ; Martin, Jody L. ; Heads, Richard J. ; Foley, Claire ; Mockridge, James W. ; Wright, Matt J. ; Wang, Yibin ; Marber, Michael S. / The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. In: FASEB Journal. 2000 ; Vol. 14, No. 14. pp. 2237-2246.
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abstract = "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-δ 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-δ, 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-δ 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 p38α or p38β. Transfected p38α and β show differential activation (P<0.001) during sustained simulated ischemia, with p38α remaining activated (1.48±0.36 vs. basal) but p38β deactivated (0.36±0.1 vs. basal, P<0.01). Prior preconditioning prevented the activation of p38α (0.65±0.11 vs. ischemia, P<0.05). Moreover, cells expressing a dominant negative p38α, 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 p38α activation during ischemia reduces injury and may contribute to preconditioning-induced cardioprotection in this model.",
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Saurin, AT, Martin, JL, Heads, RJ, Foley, C, Mockridge, JW, Wright, MJ, Wang, Y & Marber, MS 2000, 'The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes', FASEB Journal, vol. 14, no. 14, pp. 2237-2246.

The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. / Saurin, Adrian T.; Martin, Jody L.; Heads, Richard J.; Foley, Claire; Mockridge, James W.; Wright, Matt J.; Wang, Yibin; Marber, Michael S.

In: FASEB Journal, Vol. 14, No. 14, 01.11.2000, p. 2237-2246.

Research output: Contribution to journalArticle

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T1 - The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes

AU - Saurin, Adrian T.

AU - Martin, Jody L.

AU - Heads, Richard J.

AU - Foley, Claire

AU - Mockridge, James W.

AU - Wright, Matt J.

AU - Wang, Yibin

AU - Marber, Michael S.

PY - 2000/11/1

Y1 - 2000/11/1

N2 - 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-δ 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-δ, 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-δ 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 p38α or p38β. Transfected p38α and β show differential activation (P<0.001) during sustained simulated ischemia, with p38α remaining activated (1.48±0.36 vs. basal) but p38β deactivated (0.36±0.1 vs. basal, P<0.01). Prior preconditioning prevented the activation of p38α (0.65±0.11 vs. ischemia, P<0.05). Moreover, cells expressing a dominant negative p38α, 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 p38α activation during ischemia reduces injury and may contribute to preconditioning-induced cardioprotection in this model.

AB - 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-δ 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-δ, 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-δ 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 p38α or p38β. Transfected p38α and β show differential activation (P<0.001) during sustained simulated ischemia, with p38α remaining activated (1.48±0.36 vs. basal) but p38β deactivated (0.36±0.1 vs. basal, P<0.01). Prior preconditioning prevented the activation of p38α (0.65±0.11 vs. ischemia, P<0.05). Moreover, cells expressing a dominant negative p38α, 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 p38α activation during ischemia reduces injury and may contribute to preconditioning-induced cardioprotection in this model.

KW - Cardioprotection

KW - Cytoprotection

KW - Ischemic preconditioning

KW - Myocardial ischemia

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Saurin AT, Martin JL, Heads RJ, Foley C, Mockridge JW, Wright MJ et al. The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. FASEB Journal. 2000 Nov 1;14(14):2237-2246.