Loss of ischaemic preconditioning in ovariectomized rat hearts

Possible involvement of impaired protein kinase C ε phosphorylation

Ken Shinmura, Maiko Nagai, Kayoko Tamaki, Roberto Bolli

Research output: Contribution to journalArticle

Abstract

Aims: The aims of this study were to determine whether chronic oestrogen withdrawal influences the development of ischaemic preconditioning (IPC) in female hearts, to investigate the mechanism whereby IPC is impaired, and to assess whether direct activation of protein kinase C (PKC) can mimic IPC in female hearts with chronic oestrogen depletion. Methods and results: We performed Sham-operation (Sham) or bilateral ovariectomy on 16-week-old Sprague-Dawley female rats. Ovariectomized rats were randomized to subcutaneous implantation of 17β-estradiol (OxE) or placebo (OxP) pellets. Four weeks later, isolated, perfused hearts were subjected to 30 min of ischaemia followed by 120 min of reperfusion with or without three cycles of 5 min ischaemia/5 min reperfusion. The cardioprotective effect of IPC was completely lost in the OxP group. Western immunoblots revealed that in the OxP group, IPC failed to translocate PKCε to the membranous fraction and that phosphorylation of PKCε (Ser729) and phosphoinositide-dependent kinase (PDK) 1 (Ser241) was impaired. Oestrogen replacement restored the IPC effect, the translocation and phosphorylation of PKCε, and the phosphorylation of PDK1. In the OxP group, pre-treatment with a PKCε selective activator peptide (Ψ-εRACK) mimicked the IPC effect. Pre-treatment with a phosphatidylinositol-3 kinase inhibitor before IPC abrogated the translocation and phosphorylation of PKCε in the Sham group. Conclusions: The cardioprotective effect of IPC is lost in female hearts with chronic oestrogen withdrawal and this is due, at least in part, to impaired translocation and phosphorylation of PKCε. Selective activation of PKCε-mediated signalling can fully restore the IPC effect in a manner analogous to oestrogen replacement.

Original languageEnglish (US)
Pages (from-to)387-394
Number of pages8
JournalCardiovascular Research
Volume79
Issue number3
DOIs
StatePublished - Aug 2008
Externally publishedYes

Fingerprint

Ischemic Preconditioning
Protein Kinase C
Phosphorylation
Placebos
Estrogens
Estrogen Replacement Therapy
Reperfusion
Ischemia
Phosphatidylinositol 3-Kinase
1-Phosphatidylinositol 4-Kinase
Ovariectomy
Sprague Dawley Rats
Estradiol
Western Blotting

Keywords

  • Gender
  • Myocardial infarction
  • Oestrogen
  • Protein kinase C
  • Reperfusion injury

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Loss of ischaemic preconditioning in ovariectomized rat hearts : Possible involvement of impaired protein kinase C ε phosphorylation. / Shinmura, Ken; Nagai, Maiko; Tamaki, Kayoko; Bolli, Roberto.

In: Cardiovascular Research, Vol. 79, No. 3, 08.2008, p. 387-394.

Research output: Contribution to journalArticle

Shinmura, Ken ; Nagai, Maiko ; Tamaki, Kayoko ; Bolli, Roberto. / Loss of ischaemic preconditioning in ovariectomized rat hearts : Possible involvement of impaired protein kinase C ε phosphorylation. In: Cardiovascular Research. 2008 ; Vol. 79, No. 3. pp. 387-394.
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abstract = "Aims: The aims of this study were to determine whether chronic oestrogen withdrawal influences the development of ischaemic preconditioning (IPC) in female hearts, to investigate the mechanism whereby IPC is impaired, and to assess whether direct activation of protein kinase C (PKC) can mimic IPC in female hearts with chronic oestrogen depletion. Methods and results: We performed Sham-operation (Sham) or bilateral ovariectomy on 16-week-old Sprague-Dawley female rats. Ovariectomized rats were randomized to subcutaneous implantation of 17β-estradiol (OxE) or placebo (OxP) pellets. Four weeks later, isolated, perfused hearts were subjected to 30 min of ischaemia followed by 120 min of reperfusion with or without three cycles of 5 min ischaemia/5 min reperfusion. The cardioprotective effect of IPC was completely lost in the OxP group. Western immunoblots revealed that in the OxP group, IPC failed to translocate PKCε to the membranous fraction and that phosphorylation of PKCε (Ser729) and phosphoinositide-dependent kinase (PDK) 1 (Ser241) was impaired. Oestrogen replacement restored the IPC effect, the translocation and phosphorylation of PKCε, and the phosphorylation of PDK1. In the OxP group, pre-treatment with a PKCε selective activator peptide (Ψ-εRACK) mimicked the IPC effect. Pre-treatment with a phosphatidylinositol-3 kinase inhibitor before IPC abrogated the translocation and phosphorylation of PKCε in the Sham group. Conclusions: The cardioprotective effect of IPC is lost in female hearts with chronic oestrogen withdrawal and this is due, at least in part, to impaired translocation and phosphorylation of PKCε. Selective activation of PKCε-mediated signalling can fully restore the IPC effect in a manner analogous to oestrogen replacement.",
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AU - Bolli, Roberto

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N2 - Aims: The aims of this study were to determine whether chronic oestrogen withdrawal influences the development of ischaemic preconditioning (IPC) in female hearts, to investigate the mechanism whereby IPC is impaired, and to assess whether direct activation of protein kinase C (PKC) can mimic IPC in female hearts with chronic oestrogen depletion. Methods and results: We performed Sham-operation (Sham) or bilateral ovariectomy on 16-week-old Sprague-Dawley female rats. Ovariectomized rats were randomized to subcutaneous implantation of 17β-estradiol (OxE) or placebo (OxP) pellets. Four weeks later, isolated, perfused hearts were subjected to 30 min of ischaemia followed by 120 min of reperfusion with or without three cycles of 5 min ischaemia/5 min reperfusion. The cardioprotective effect of IPC was completely lost in the OxP group. Western immunoblots revealed that in the OxP group, IPC failed to translocate PKCε to the membranous fraction and that phosphorylation of PKCε (Ser729) and phosphoinositide-dependent kinase (PDK) 1 (Ser241) was impaired. Oestrogen replacement restored the IPC effect, the translocation and phosphorylation of PKCε, and the phosphorylation of PDK1. In the OxP group, pre-treatment with a PKCε selective activator peptide (Ψ-εRACK) mimicked the IPC effect. Pre-treatment with a phosphatidylinositol-3 kinase inhibitor before IPC abrogated the translocation and phosphorylation of PKCε in the Sham group. Conclusions: The cardioprotective effect of IPC is lost in female hearts with chronic oestrogen withdrawal and this is due, at least in part, to impaired translocation and phosphorylation of PKCε. Selective activation of PKCε-mediated signalling can fully restore the IPC effect in a manner analogous to oestrogen replacement.

AB - Aims: The aims of this study were to determine whether chronic oestrogen withdrawal influences the development of ischaemic preconditioning (IPC) in female hearts, to investigate the mechanism whereby IPC is impaired, and to assess whether direct activation of protein kinase C (PKC) can mimic IPC in female hearts with chronic oestrogen depletion. Methods and results: We performed Sham-operation (Sham) or bilateral ovariectomy on 16-week-old Sprague-Dawley female rats. Ovariectomized rats were randomized to subcutaneous implantation of 17β-estradiol (OxE) or placebo (OxP) pellets. Four weeks later, isolated, perfused hearts were subjected to 30 min of ischaemia followed by 120 min of reperfusion with or without three cycles of 5 min ischaemia/5 min reperfusion. The cardioprotective effect of IPC was completely lost in the OxP group. Western immunoblots revealed that in the OxP group, IPC failed to translocate PKCε to the membranous fraction and that phosphorylation of PKCε (Ser729) and phosphoinositide-dependent kinase (PDK) 1 (Ser241) was impaired. Oestrogen replacement restored the IPC effect, the translocation and phosphorylation of PKCε, and the phosphorylation of PDK1. In the OxP group, pre-treatment with a PKCε selective activator peptide (Ψ-εRACK) mimicked the IPC effect. Pre-treatment with a phosphatidylinositol-3 kinase inhibitor before IPC abrogated the translocation and phosphorylation of PKCε in the Sham group. Conclusions: The cardioprotective effect of IPC is lost in female hearts with chronic oestrogen withdrawal and this is due, at least in part, to impaired translocation and phosphorylation of PKCε. Selective activation of PKCε-mediated signalling can fully restore the IPC effect in a manner analogous to oestrogen replacement.

KW - Gender

KW - Myocardial infarction

KW - Oestrogen

KW - Protein kinase C

KW - Reperfusion injury

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