Novel functional role of heat shock protein 90 in ATP-sensitive K+ channel-mediated hypoxic preconditioning.
OBJECTIVE
ATP-sensitive K+ (K ATP) 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 K ATP channels protect the heart is still largely unknown. The present study was designed to explore the potential mechanism involved in K ATP channel-mediated cardioprotection.


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 K ATP 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.


CONCLUSIONS
We demonstrate that Kir6.2 is critical in HP of cardiomyocytes. Importantly, we show that HSP90 is involved in K ATP-mediated cytoprotection, possibly by promoting mitochondrial targeting of Kir6.2.
Jiao
Jun-Dong
JD
Division of Pharmacology, College of Pharmacy, The Ohio State University, 530 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210, USA.
Garg
Vivek
V
Yang
Baofeng
B
Hu
Keli
K
D000818:Animals; D002478:Cells, Cultured; D019610:Cytoprotection; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D019194:Ischemic Preconditioning; D054086:KATP Channels / Q000502:physiology*; D008929:Mitochondria, Heart / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D051381:Rats; D000099161:Kcnj11 Channel
D018841:HSP90 Heat-Shock Proteins; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel