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Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 4, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm028
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Novel functional role of heat shock protein 90 in ATP-sensitive K+ channel-mediated hypoxic preconditioning

Jun-dong Jiao*,¶, Vivek Garg*,¶, Baofeng Yang§ and Keli Hu,{ddagger},1

Division of Pharmacology, College of Pharmacy
{ddagger} Institute of Mitochondrial Biology, The Ohio State University, Columbus, OH, 43210, U.S.A.
§ Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, 150086, China

1 Address for Correspondence: Keli Hu, MD, Ph.D. 530 Parks Hall Division of Pharmacology, College of Pharmacy 500 West 12th Avenue The Ohio State University Columbus, OH, 43210 Tel. 614-292-5433, Fax. 614-292-9083 E-mail: hu.175{at}osu.edu

Aims: ATP-sensitive K+ channels (KATP) are implicated in the protective effect of ischemic preconditioning (IPC). Kir6.2 has been shown to be involved in the cardioprotection of ischemic preconditioning. 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: Cellular models of hypoxic preconditioning from rat heart-derived H9c2 cells and adult rat cardiomyocytes were employed. Dominant negative and siRNA technology were utilized in combination with biochemical, immunofluorescent and cell viability assays.

Results: The cell viability study revealed that hypoxic preconditioning 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 hypoxic preconditioning. We found that HSP90 was associated with Kir6.2 and its activity was linked to mitochondrial targeting of Kir6.2.

Conclusions: We demonstrate that Kir6.2 is critical in hypoxic preconditioning 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

* Both authors contributed equally to this work.


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V. Garg, J. Jiao, and K. Hu
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[Abstract] [Full Text] [PDF]


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