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Cardiovascular Research Advance Access originally published online on October 4, 2007
Cardiovascular Research 2008 77(1):126-133; doi:10.1093/cvr/cvm028
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Novel functional role of heat shock protein 90 in ATP-sensitive K+ channel-mediated hypoxic preconditioning

Jun-Dong Jiao1,{dagger}, Vivek Garg1,{dagger}, Baofeng Yang2 and Keli Hu1,3,*

1 Division of Pharmacology, College of Pharmacy, The Ohio State University, 530 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210, USA
2 Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang 150086, China
3 Institute of Mitochondrial Biology, The Ohio State University, Columbus, OH 43210, USA

* Corresponding author. Tel: +1 614 292 5433; fax: +1 614 292 9083. E-mail address: hu.175{at}osu.edu

Aims: ATP-sensitive K+ (KATP) channels are implicated in the protective effect of ischaemic preconditioning (IPC). Kir6.2 has been shown to be involved in the cardioprotection of IPC. However, the mechanism by which Kir6.2-containing KATP channels protect the heart is still largely unknown. The present study was designed to explore the potential mechanism involved in KATP channel-mediated cardioprotection.

Methods and results: Cellular models of hypoxic preconditioning (HP) from rat heart-derived H9c2 cells and adult rat cardiomyocytes were employed. Dominant negative and small interfering RNA (siRNA) technology were utilized in combination with biochemical, immunofluorescent, and cell viability assays. The cell viability study revealed that HP significantly increased the viable cells after prolonged hypoxia and reoxygenation. This protective effect was prevented by expression of dominant negative Kir6.2AAA, siRNA targeting Kir6.2, or the KATP channel inhibitor 5-hydroxydecanoate. Further, our data showed that inhibiting heat shock protein 90 (HSP90) function with the HSP90 inhibitor geldanamycin or HSP90 expression with siRNA completely inhibited the protection of HP. We found that HSP90 was associated with Kir6.2 and its activity was linked to mitochondrial targeting of Kir6.2.

Conclusion: We demonstrate that Kir6.2 is critical in HP of cardiomyocytes. Importantly, we show that HSP90 is involved in KATP-mediated cytoprotection, possibly by promoting mitochondrial targeting of Kir6.2.

KEYWORDS Preconditioning; K-ATP channel; Mitochondria; Heat shock protein

Time for primary review: 31 days

{dagger} These authors contributed equally to this work.


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