Role of protein kinase C in mitochondrial K(ATP) channel-mediated protection against CA2+ overload injury in rat myocardium

Yigang Wang, Muhammad Ashraf

Research output: Contribution to journalArticle

161 Citations (Scopus)

Abstract

Growing evidence exists that ATP-sensitive mitochondrial potassium channels (MitoK(ATP) channel) are a major contributor to the cardiac protection against ischemia. Given the importance of mitochondria in the cardiac cell, we tested whether the potent and specific opener of the MitoK(ATP) channel diazoxide attenuates the lethal injury associated with Ca2+ overload. The specific aims of this study were to test whether protection by diazoxide is mediated by MitoK(ATP) channels; whether diazoxide mimics the effects of Ca2+ preconditioning; and whether diazoxide reduces Ca2+ paradox (PD) injury via protein kinase C (PKC) signaling pathways. Langendorff-perfused rat hearts were subjected to the Ca2+ PD (10 minutes of Ca2+ depletion followed by 10 minutes of Ca2+ repletion). The effects of the MitoK(ATP) channel and other interventions on functional, biochemical, and pathological changes in hearts subjected to Ca2+ PD were assessed. In hearts treated with 80 μmol/L diazoxide, left ventricular end-diastolic pressure and coronary flow were significantly preserved after Ca2+ PD; peak lactate dehydrogenase release was also significantly decreased, although ATP content was less depleted. The cellular structures were well preserved, including mitochondria and intercalated disks in diazoxide-treated hearts compared with nontreated Ca2+ PD hearts. The salutary effects of diazoxide on the Ca2+ PD injury were similar to those in hearts that underwent Ca2+ preconditioning or pretreatment with phorbol 12-myristate 13-acetate before Ca2+ PD. The addition of sodium 5-hydroxydecanoate, a specific MitOK(ATP) channel inhibitor, or chelerythrine chloride, a PKC inhibitor, during diazoxide pretreatment completely abolished the beneficial effects of diazoxide on the Ca2+ PD. Blockade of Ca2+ entry during diazoxide treatment by inhibiting L-type Ca2+ channel with verapamil or nifedipine also completely reversed the beneficial effects of diazoxide on the Ca2+ PD. PKC-δ was translocated to the mitochondria, intercalated disks, and nuclei of myocytes in diazoxide-pretreated hearts, and PKC-α and PKC-ε were translocated to sarcolemma and intercalated disks, respectively. This study suggests that the effect of the MitoK(ATP) channel is mediated by PKC- mediated signaling pathway.

Original languageEnglish (US)
Pages (from-to)1156-1165
Number of pages10
JournalCirculation research
Volume84
Issue number10
DOIs
StatePublished - May 28 1999
Externally publishedYes

Fingerprint

Diazoxide
Protein Kinase C
Myocardium
Wounds and Injuries
Mitochondria
mitochondrial K(ATP) channel
Adenosine Triphosphate
KATP Channels
Sarcolemma
Protein C Inhibitor
Cellular Structures
Nifedipine
Protein Kinase Inhibitors
Verapamil
L-Lactate Dehydrogenase
Muscle Cells
Acetates

Keywords

  • Ca paradox
  • Ca preconditioning
  • Diazoxide
  • K channel
  • Protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Role of protein kinase C in mitochondrial K(ATP) channel-mediated protection against CA2+ overload injury in rat myocardium. / Wang, Yigang; Ashraf, Muhammad.

In: Circulation research, Vol. 84, No. 10, 28.05.1999, p. 1156-1165.

Research output: Contribution to journalArticle

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