Targeted disruption of the protein kinase C epsilon gene abolishes the infarct size reduction that follows ischaemic preconditioning of isolated buffer-perfused mouse hearts

Adrian T. Saurin, Daniel J. Pennington, Nicolaas J.H. Raat, David S. Latchman, Michael J. Owen, Michael S. Marber

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Objective: Activation of protein kinase C (PKC) isoforms is associated with the cardioprotective effect of early ischaemic preconditioning (IP). PKC consists of at least 10 different isoforms, encoded by separate genes, which mediate distinct physiological functions. Although the PKC-ε isoform has been implicated in preconditioning, uncertainty remains. We investigated whether preconditioning still occurs in a mouse line lacking cardiac PKC-ε protein due to a targeted disruption within the pkc-ε allele.

Methods: The isolated buffer-perfused hearts from knockout mice lacking PKC-ε (-/-) and sibling heterozygous mice (+/-), with a normal PKC-ε complement, were preconditioned by 4×4 min ischaemia/6 min reperfusion. Hearts then underwent 45 min of global ischaemia followed by 1.5 h of reperfusion.

Results: In PKC-ε (+/-) hearts ischaemic preconditioning reduced infarction volume as a percentage of myocardial volume (24.3±4.5 vs. 41.3±4.7%, P<0.001). In contrast, in PKC-ε (-/-) hearts preconditioning failed to diminish infarction (36.4±2.9 vs. 38.8±4.5%). Surprisingly however, although preconditioning did not reduce infarct size, it did enhance contractile recovery in PKC-ε (-/-) mice (43.1±3.9 vs. 24.9±5.1%, P<0.05), similar to the level seen in PKC-ε (+/-) hearts (35.2±3.9 vs. 20.9±5.0%, P<0.05).

Conclusions: These data suggest that PKC-ε is essential for the reduction in infarction that follows early ischaemic preconditioning, but is not associated with the improvement in functional recovery.

Original languageEnglish
Pages (from-to)672-680
Number of pages9
JournalCardiovascular Research
Volume55
Issue number3
DOIs
Publication statusPublished - 15 Aug 2002

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Protein Kinase C-epsilon
Ischemic Preconditioning
Protein Kinase C
Buffers
Genes
Infarction
Protein Isoforms
Reperfusion
Ischemia
Knockout Mice
Uncertainty

Keywords

  • Ischemia
  • Preconditioning
  • Protein kinases

Cite this

Saurin, Adrian T. ; Pennington, Daniel J. ; Raat, Nicolaas J.H. ; Latchman, David S. ; Owen, Michael J. ; Marber, Michael S. / Targeted disruption of the protein kinase C epsilon gene abolishes the infarct size reduction that follows ischaemic preconditioning of isolated buffer-perfused mouse hearts. In: Cardiovascular Research. 2002 ; Vol. 55, No. 3. pp. 672-680.
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abstract = "Objective: Activation of protein kinase C (PKC) isoforms is associated with the cardioprotective effect of early ischaemic preconditioning (IP). PKC consists of at least 10 different isoforms, encoded by separate genes, which mediate distinct physiological functions. Although the PKC-ε isoform has been implicated in preconditioning, uncertainty remains. We investigated whether preconditioning still occurs in a mouse line lacking cardiac PKC-ε protein due to a targeted disruption within the pkc-ε allele.Methods: The isolated buffer-perfused hearts from knockout mice lacking PKC-ε (-/-) and sibling heterozygous mice (+/-), with a normal PKC-ε complement, were preconditioned by 4×4 min ischaemia/6 min reperfusion. Hearts then underwent 45 min of global ischaemia followed by 1.5 h of reperfusion.Results: In PKC-ε (+/-) hearts ischaemic preconditioning reduced infarction volume as a percentage of myocardial volume (24.3±4.5 vs. 41.3±4.7{\%}, P<0.001). In contrast, in PKC-ε (-/-) hearts preconditioning failed to diminish infarction (36.4±2.9 vs. 38.8±4.5{\%}). Surprisingly however, although preconditioning did not reduce infarct size, it did enhance contractile recovery in PKC-ε (-/-) mice (43.1±3.9 vs. 24.9±5.1{\%}, P<0.05), similar to the level seen in PKC-ε (+/-) hearts (35.2±3.9 vs. 20.9±5.0{\%}, P<0.05).Conclusions: These data suggest that PKC-ε is essential for the reduction in infarction that follows early ischaemic preconditioning, but is not associated with the improvement in functional recovery.",
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Targeted disruption of the protein kinase C epsilon gene abolishes the infarct size reduction that follows ischaemic preconditioning of isolated buffer-perfused mouse hearts. / Saurin, Adrian T.; Pennington, Daniel J.; Raat, Nicolaas J.H.; Latchman, David S.; Owen, Michael J.; Marber, Michael S.

In: Cardiovascular Research, Vol. 55, No. 3, 15.08.2002, p. 672-680.

Research output: Contribution to journalArticle

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T1 - Targeted disruption of the protein kinase C epsilon gene abolishes the infarct size reduction that follows ischaemic preconditioning of isolated buffer-perfused mouse hearts

AU - Saurin, Adrian T.

AU - Pennington, Daniel J.

AU - Raat, Nicolaas J.H.

AU - Latchman, David S.

AU - Owen, Michael J.

AU - Marber, Michael S.

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N2 - Objective: Activation of protein kinase C (PKC) isoforms is associated with the cardioprotective effect of early ischaemic preconditioning (IP). PKC consists of at least 10 different isoforms, encoded by separate genes, which mediate distinct physiological functions. Although the PKC-ε isoform has been implicated in preconditioning, uncertainty remains. We investigated whether preconditioning still occurs in a mouse line lacking cardiac PKC-ε protein due to a targeted disruption within the pkc-ε allele.Methods: The isolated buffer-perfused hearts from knockout mice lacking PKC-ε (-/-) and sibling heterozygous mice (+/-), with a normal PKC-ε complement, were preconditioned by 4×4 min ischaemia/6 min reperfusion. Hearts then underwent 45 min of global ischaemia followed by 1.5 h of reperfusion.Results: In PKC-ε (+/-) hearts ischaemic preconditioning reduced infarction volume as a percentage of myocardial volume (24.3±4.5 vs. 41.3±4.7%, P<0.001). In contrast, in PKC-ε (-/-) hearts preconditioning failed to diminish infarction (36.4±2.9 vs. 38.8±4.5%). Surprisingly however, although preconditioning did not reduce infarct size, it did enhance contractile recovery in PKC-ε (-/-) mice (43.1±3.9 vs. 24.9±5.1%, P<0.05), similar to the level seen in PKC-ε (+/-) hearts (35.2±3.9 vs. 20.9±5.0%, P<0.05).Conclusions: These data suggest that PKC-ε is essential for the reduction in infarction that follows early ischaemic preconditioning, but is not associated with the improvement in functional recovery.

AB - Objective: Activation of protein kinase C (PKC) isoforms is associated with the cardioprotective effect of early ischaemic preconditioning (IP). PKC consists of at least 10 different isoforms, encoded by separate genes, which mediate distinct physiological functions. Although the PKC-ε isoform has been implicated in preconditioning, uncertainty remains. We investigated whether preconditioning still occurs in a mouse line lacking cardiac PKC-ε protein due to a targeted disruption within the pkc-ε allele.Methods: The isolated buffer-perfused hearts from knockout mice lacking PKC-ε (-/-) and sibling heterozygous mice (+/-), with a normal PKC-ε complement, were preconditioned by 4×4 min ischaemia/6 min reperfusion. Hearts then underwent 45 min of global ischaemia followed by 1.5 h of reperfusion.Results: In PKC-ε (+/-) hearts ischaemic preconditioning reduced infarction volume as a percentage of myocardial volume (24.3±4.5 vs. 41.3±4.7%, P<0.001). In contrast, in PKC-ε (-/-) hearts preconditioning failed to diminish infarction (36.4±2.9 vs. 38.8±4.5%). Surprisingly however, although preconditioning did not reduce infarct size, it did enhance contractile recovery in PKC-ε (-/-) mice (43.1±3.9 vs. 24.9±5.1%, P<0.05), similar to the level seen in PKC-ε (+/-) hearts (35.2±3.9 vs. 20.9±5.0%, P<0.05).Conclusions: These data suggest that PKC-ε is essential for the reduction in infarction that follows early ischaemic preconditioning, but is not associated with the improvement in functional recovery.

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