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Cardiovascular Research Advance Access first published online on April 4, 2008
This version [Corrected Proof] published online on April 25, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn086
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Loss of ischaemic pre-conditioning in ovariectomized rat hearts: possible involvement of impaired protein kinase C {varepsilon} phosphorylation

Ken Shinmura1,*, Maiko Nagai1, Kayoko Tamaki1 and Roberto Bolli2

1 Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
2 The Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA

* Corresponding author. Tel: +81 3 3353 1211 ext. 62915; fax: +81 3 5269 2468. E-mail address: shimmura{at}sc.itc.keio.ac.jp

Aims: The aims of this study were to determine whether chronic oestrogen withdrawal influences the development of ischaemic pre-conditioning (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 PKC{varepsilon} to the membranous fraction and that phosphorylation of PKC{varepsilon} (Ser729) and phosphoinositide-dependent kinase (PDK) 1 (Ser241) was impaired. Oestrogen replacement restored the IPC effect, the translocation and phosphorylation of PKC{varepsilon}, and the phosphorylation of PDK1. In the OxP group, pre-treatment with a PKC{varepsilon} selective activator peptide ({Psi}–{varepsilon}RACK) mimicked the IPC effect. Pre-treatment with a phosphatidylinositol-3 kinase inhibitor before IPC abrogated the translocation and phosphorylation of PKC{varepsilon} 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 PKC{varepsilon}. Selective activation of PKC{varepsilon}-mediated signalling can fully restore the IPC effect in a manner analogous to oestrogen replacement.

KEYWORDS Oestrogen; Gender; Myocardial infarction; Protein kinase C; Reperfusion injury

Time for primary review: 28 days


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