P87Activation of mitogen and stress activated kinase 1 (MSK1) during oxidative stress modulates apoptotic and autophagy pathways leading to cardioprotection

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Background and purpose: Oxidative stress promotes cardiac myocyte death and it is a key factor in the development of various cardiovascular diseases. Several signaling pathways have been implicated in the response of cardiac myocytes to oxidative stress including the MAPKs. Mitogen- and stress-activated protein kinase (MSK1) plays an important role in the regulation of transcription downstream of ERK1/2 and p38 MAPK while its role in the heart is less clear yet. In this study we sought to investigate the role of MSK1 in the response of cardiac myocytes during oxidative stress.

Methods/Results: Perfused rat hearts were subjected to ischemia/reperfusion (I/R) and isolated adult cardiac myocytes were exposed to simulated ischemia (SI). Increased phosphorylation of MSK1 was observed after ischemia. Inhibition of MSK1 using the specific inhibitor SB747651A resulted in reduction of cell viability and increased apoptosis. At the same time, the anti-apoptotic Bcl-2 protein was downregulated. Autophagy associated proteins (LC3BI-II, p62) were also determined by immunoblotting. An increase in LC3BII/LC3BI ratio and a decrease of p62 was observed after inhibition of MSK1 during ischemia, indicating an increased autophagic flux.

Conclusion: The results of the study demonstrate that activation of MSK1 during oxidative stress modulates apoptotic and autophagy mechanisms in a cardioprotective manner.

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