Inhibition of JNK Mitochondrial Localization and Signaling Is Protective against Ischemia/Reperfusion Injury in Rats

Jeremy W Chambers,Alok Pachori,Shannon Howard,Sarah Iqbal,Philip V Lograsso

doi:10.1074/jbc.m112.406777

Jeremy W Chambers, Alok Pachori + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m112.406777

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Abstract

To build upon recent findings that mitochondrial JNK signaling is inhibited by selectively blocking the interaction between JNK and Sab, we utilized a cell-permeable peptide to demonstrate that ischemia/reperfusion (I/R) injury could be protected in vivo and that JNK mitochondrial signaling was the mechanism by which reactive oxygen species (ROS) generation, mitochondrial dysfunction, and cardiomyocyte cell death occur. We also demonstrated that 5 mg/kg SR-3306 (a selective JNK inhibitor) was able to protect against I/R injury, reducing infarct volume by 34% (p < 0.05) while also decreasing I/R-induced increases in the activity of creatine phosphokinase and creatine kinase-MB. TUNEL staining showed that the percent TUNEL positive nuclei in rat hearts increased 10-fold after I/R injury and that this was reduced 4-fold (p < 0.01) by SR-3306. These data suggest that blocking JNK mitochondrial translocation or JNK inhibition prevents ROS increases and mitochondrial dysfunction and may be an effective treatment for I/R-induced cardiomyocyte death.

Highlights

Little is known about the role of JNK mitochondrial signaling in cardiomyocyte cell death
To build upon recent findings that mitochondrial JNK signaling is inhibited by selectively blocking the interaction between JNK and Sab, we utilized a cell-permeable peptide to demonstrate that ischemia/reperfusion (I/R) injury could be protected in vivo and that JNK mitochondrial signaling was the mechanism by which reactive oxygen species (ROS) generation, mitochondrial dysfunction, and cardiomyocyte cell death occur
Given our recent work in which we showed that mitochondrial JNK signaling initiates physiological changes in HeLa cells stressed with anisomycin resulting in amplification of ROS [6], and the ability to selectively block the subsequent mitochondrial dysfunction and cell death associated with translocation [14], we decided to see whether these effects could be generated in cardiomyocyte-like H9c2 cells and during I/R in vivo

Summary

Introduction

Little is known about the role of JNK mitochondrial signaling in cardiomyocyte cell death. Conclusion: Blocking JNK mitochondrial translocation or JNK inhibition may be an effective treatment for I/R-induced cardiomyocyte death. To build upon recent findings that mitochondrial JNK signaling is inhibited by selectively blocking the interaction between JNK and Sab, we utilized a cell-permeable peptide to demonstrate that ischemia/reperfusion (I/R) injury could be protected in vivo and that JNK mitochondrial signaling was the mechanism by which reactive oxygen species (ROS) generation, mitochondrial dysfunction, and cardiomyocyte cell death occur. TUNEL staining showed that the percent TUNEL positive nuclei in rat hearts increased 10-fold after I/R injury and that this was reduced 4-fold (p < 0.01) by SR-3306. These data suggest that blocking JNK mitochondrial translocation or JNK inhibition prevents ROS increases and mitochondrial dysfunction and may be an effective treatment for I/R-induced cardiomyocyte death

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Results

Conclusion