Statins inhibit reoxygenation-induced cardiomyocyte apoptosis: role for glycogen synthase kinase 3beta and transcription factor beta-catenin

Journal of Molecular and Cellular Cardiology
Martin W BergmannRainer Dietz

Abstract

Statins may improve left ventricular remodeling after myocardial infarction. We tested whether statins inhibit cardiomyocyte apoptosis through glycogen synthase kinase 3beta (GSK3beta) inactivation and evaluated activation of downstream transcription factors. Mevastatin and pravastatin activated serine/threonine kinase Akt in neonatal cardiomyocytes dose and time dependently with maximal activation at 15 min/10 microM. Caspase-3 activity was induced 2.73 +/- 0.29-fold by 6 h of hypoxia followed by 18 h of reoxygenation. Pravastatin added at the beginning of the reoxygenation period reduced caspase-3 activation to 1.26 +/- 0.06-fold compared to control cells (P < 0.001). Similar results were obtained for mevastatin (decreased to 1.98 +/- 0.45-fold, P < 0.05). TUNEL staining of neonatal cardiomyocytes after 24 h reoxygenation and 4',6'-diamidino-2-phenylindole staining of adult rat cardiomyocytes after 6 h H(2)O(2) showed reduced cardiomyocyte apoptosis in the presence of statin. Analysis of signaling pathways downstream of Akt revealed phosphorylation of GSK3beta. Transcription factor cAMP-responsive element binding (CREB) protein showed weak phosphorylation at serine 133; transcription factor NF-kappaB was not significantly act...Continue Reading

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Citations

Jan 26, 2007·Proceedings of the National Academy of Sciences of the United States of America·Maria MirotsouVictor Dzau
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