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Pharmacological and ischemic preconditioning of the human myocardium: mitoK(ATP) channels are upstream and p38MAPK is downstream of PKC.

Loubani M, Galiñanes M - BMC Physiol. (2002)

Bottom Line: Similar protection was obtained with alpha1 agonist phenylephrine, adenosine and IP and their combination did not afford additional cardioprotection.Furthermore, the protection induced by PMA was abolished by SB203580 but not by 5-hydroxydecanoate, whereas the protection induced by anisomycin was unaffected by either 5-hydroxydecanoate or chelerythrine.Opening of mitoK(ATP) channels and activation of PKC and p38MAPK are obligatory steps in the signal transduction cascade of IP and PP of the human myocardium with PKC activation being downstream of the opening of mitoK(ATP) channels and upstream of p38MAPK activation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Integrative Human Cardiovascular Physiology and Functional Genomics, Division of Cardiac Surgery, University of Leicester, Glenfield Hospital, Groby Road, Leicester. mahmoud.loubani@ntlworld.com

ABSTRACT

Background: These studies investigate the role of mitoK(ATP) channels, protein kinase C (PKC) and Mitogen activated protein kinase (p38MAPK) on the cardioprotection of ischemic (IP) and pharmacological preconditioning (PP) of the human myocardium and their sequence of activation.

Results: Right atrial appendages from patients undergoing elective cardiac surgery were equilibrated for 30 min and then subjected to 90 min of simulated ischemia followed by 120 min reoxygenation. At the end of each protocol creatinine kinase leakage (CK U/g wet wt) and the reduction of MTT to formazan dye (mM/g wet wt) were measured. Similar protection was obtained with alpha1 agonist phenylephrine, adenosine and IP and their combination did not afford additional cardioprotection. Blockade of mitoK(ATP) channels with 5-hydroxydecanoate, PKC with chelerythrine, or p38MAPK with SB203580 abolished the protection of IP and of PP. In additional studies, the stimulation of mitoK(ATP) channels with diazoxide or activation of PKC with PMA or p38MAPK with anisomycin induced identical protection to that of IP and PP. The protection induced by diazoxide was abolished by blockade of PKC and by blockade of p38MAPK. Furthermore, the protection induced by PMA was abolished by SB203580 but not by 5-hydroxydecanoate, whereas the protection induced by anisomycin was unaffected by either 5-hydroxydecanoate or chelerythrine.

Conclusions: Opening of mitoK(ATP) channels and activation of PKC and p38MAPK are obligatory steps in the signal transduction cascade of IP and PP of the human myocardium with PKC activation being downstream of the opening of mitoK(ATP) channels and upstream of p38MAPK activation.

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Proposed schematic representation of the signal transduction mechanism leading to cardioprotection by pharmacological and ischemic preconditioning of the human myocardium. Upon activation of sarcolemmal receptors mitoKATP channels are opened via G proteins and possibly PKC-δ. The opening of mitoKATP channels will activate PKC possibly via the production of radical oxygen species (ROS). PKC may then translocate to various cellular sites including the mitochondria, sarcolemma and intercalated discs, and nucleus, a phenomenon that may involve specific PKC isoforms, where p38MAPK will be activated. In turn, p38MAPK may activate a single or multiple end-effectors directly or via MAPK intermediates. PLC: phospholipase C, PLD: phospholipase D.
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Figure 7: Proposed schematic representation of the signal transduction mechanism leading to cardioprotection by pharmacological and ischemic preconditioning of the human myocardium. Upon activation of sarcolemmal receptors mitoKATP channels are opened via G proteins and possibly PKC-δ. The opening of mitoKATP channels will activate PKC possibly via the production of radical oxygen species (ROS). PKC may then translocate to various cellular sites including the mitochondria, sarcolemma and intercalated discs, and nucleus, a phenomenon that may involve specific PKC isoforms, where p38MAPK will be activated. In turn, p38MAPK may activate a single or multiple end-effectors directly or via MAPK intermediates. PLC: phospholipase C, PLD: phospholipase D.

Mentions: The diagram in Figure 7 describes our proposal of the signal transduction cascade of preconditioning in the human myocardium. It is suggested that upon activation of sarcolemmal receptors (e.g. adenosine receptors, α1-adrenoreceptors) mitoKATP channels are opened via Gi proteins and PKC, possibly PKC-δ [28]. The opening of mitoKATP channels will activate PKC possibly via the production of radical oxygen species [18]. PKC may then translocate to various cellular sites including the mitochondria, sarcolemma and intercalated discs, and nucleus, a phenomena that may involve specific PKC isoforms, where p38MAPK will be activated. In turn, p38MAPK may activate a simple or multiple end-effectors directly or via MAPK intermediates. It is clear that more studies are required to fully elucidate the signal transduction pathway of preconditioning and the coupling between its components.


Pharmacological and ischemic preconditioning of the human myocardium: mitoK(ATP) channels are upstream and p38MAPK is downstream of PKC.

Loubani M, Galiñanes M - BMC Physiol. (2002)

Proposed schematic representation of the signal transduction mechanism leading to cardioprotection by pharmacological and ischemic preconditioning of the human myocardium. Upon activation of sarcolemmal receptors mitoKATP channels are opened via G proteins and possibly PKC-δ. The opening of mitoKATP channels will activate PKC possibly via the production of radical oxygen species (ROS). PKC may then translocate to various cellular sites including the mitochondria, sarcolemma and intercalated discs, and nucleus, a phenomenon that may involve specific PKC isoforms, where p38MAPK will be activated. In turn, p38MAPK may activate a single or multiple end-effectors directly or via MAPK intermediates. PLC: phospholipase C, PLD: phospholipase D.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC117790&req=5

Figure 7: Proposed schematic representation of the signal transduction mechanism leading to cardioprotection by pharmacological and ischemic preconditioning of the human myocardium. Upon activation of sarcolemmal receptors mitoKATP channels are opened via G proteins and possibly PKC-δ. The opening of mitoKATP channels will activate PKC possibly via the production of radical oxygen species (ROS). PKC may then translocate to various cellular sites including the mitochondria, sarcolemma and intercalated discs, and nucleus, a phenomenon that may involve specific PKC isoforms, where p38MAPK will be activated. In turn, p38MAPK may activate a single or multiple end-effectors directly or via MAPK intermediates. PLC: phospholipase C, PLD: phospholipase D.
Mentions: The diagram in Figure 7 describes our proposal of the signal transduction cascade of preconditioning in the human myocardium. It is suggested that upon activation of sarcolemmal receptors (e.g. adenosine receptors, α1-adrenoreceptors) mitoKATP channels are opened via Gi proteins and PKC, possibly PKC-δ [28]. The opening of mitoKATP channels will activate PKC possibly via the production of radical oxygen species [18]. PKC may then translocate to various cellular sites including the mitochondria, sarcolemma and intercalated discs, and nucleus, a phenomena that may involve specific PKC isoforms, where p38MAPK will be activated. In turn, p38MAPK may activate a simple or multiple end-effectors directly or via MAPK intermediates. It is clear that more studies are required to fully elucidate the signal transduction pathway of preconditioning and the coupling between its components.

Bottom Line: Similar protection was obtained with alpha1 agonist phenylephrine, adenosine and IP and their combination did not afford additional cardioprotection.Furthermore, the protection induced by PMA was abolished by SB203580 but not by 5-hydroxydecanoate, whereas the protection induced by anisomycin was unaffected by either 5-hydroxydecanoate or chelerythrine.Opening of mitoK(ATP) channels and activation of PKC and p38MAPK are obligatory steps in the signal transduction cascade of IP and PP of the human myocardium with PKC activation being downstream of the opening of mitoK(ATP) channels and upstream of p38MAPK activation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Integrative Human Cardiovascular Physiology and Functional Genomics, Division of Cardiac Surgery, University of Leicester, Glenfield Hospital, Groby Road, Leicester. mahmoud.loubani@ntlworld.com

ABSTRACT

Background: These studies investigate the role of mitoK(ATP) channels, protein kinase C (PKC) and Mitogen activated protein kinase (p38MAPK) on the cardioprotection of ischemic (IP) and pharmacological preconditioning (PP) of the human myocardium and their sequence of activation.

Results: Right atrial appendages from patients undergoing elective cardiac surgery were equilibrated for 30 min and then subjected to 90 min of simulated ischemia followed by 120 min reoxygenation. At the end of each protocol creatinine kinase leakage (CK U/g wet wt) and the reduction of MTT to formazan dye (mM/g wet wt) were measured. Similar protection was obtained with alpha1 agonist phenylephrine, adenosine and IP and their combination did not afford additional cardioprotection. Blockade of mitoK(ATP) channels with 5-hydroxydecanoate, PKC with chelerythrine, or p38MAPK with SB203580 abolished the protection of IP and of PP. In additional studies, the stimulation of mitoK(ATP) channels with diazoxide or activation of PKC with PMA or p38MAPK with anisomycin induced identical protection to that of IP and PP. The protection induced by diazoxide was abolished by blockade of PKC and by blockade of p38MAPK. Furthermore, the protection induced by PMA was abolished by SB203580 but not by 5-hydroxydecanoate, whereas the protection induced by anisomycin was unaffected by either 5-hydroxydecanoate or chelerythrine.

Conclusions: Opening of mitoK(ATP) channels and activation of PKC and p38MAPK are obligatory steps in the signal transduction cascade of IP and PP of the human myocardium with PKC activation being downstream of the opening of mitoK(ATP) channels and upstream of p38MAPK activation.

Show MeSH
Related in: MedlinePlus