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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 4, 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 Ischemic Preconditioning in Ovariectomized Rat Hearts: Possible Involvement of Impaired PKC{varepsilon} Phosphorylation

Ken Shinmura1, Maiko Nagai1, Kayoko Tamaki1 and Roberto Bolli2

1 Department of Internal Medicine, Keio University School of Medicine, Tokyo, JAPAN
2 The Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA

Address for correspondence: Ken Shinmura, MD, PhD Department of Internal Medicine, Keio University School of Medicine 35 Shinanomachi, Shinjuku-ku Tokyo, JAPAN 160-8582 Telephone: +81-(3)-3353-1211 Ext. 62915 Fax: +81-(3)-5269-2468 E-mail: shimmura{at}sc.itc.keio.ac.jp

AIMS: The aims of this study were to determine whether chronic estrogen withdrawal influences the development of ischemic 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 estrogen depletion.

METHODS: 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 ischemia followed by 120 min of reperfusion with or without 3 cycles of 5 min ischemia/5 min reperfusion.

RESULTS: 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 of phosphoinositide-dependent kinase (PDK)1 (Ser241) was impaired. Estrogen replacement restored the IPC effect, the translocation and phosphorylation of PKC {varepsilon}, and the phosphorylation of PDK1. In the OxP group, pretreatment with a PKC {varepsilon} selective activator peptide ({Psi}-{varepsilon}RACK) mimicked the IPC effect. Pretreatment 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 estrogen withdrawal, and this is due, at least in part, to impaired translocation and phosphorylation of PKC {varepsilon}. Selective activation of PKC {varepsilon}-mediated signaling can fully restore the IPC effect, in a manner analogous to estrogen replacement.

Time for primary review: 28 days


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