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

Item Type:Article
Title:Statins inhibit reoxygenation-induced cardiomyocyte apoptosis: role for glycogen synthase kinase 3beta and transcription factor beta-catenin
Creators Name:Bergmann, M.W. and Rechner, C. and Freund, C. and Baurand, A. and El Jamali, A. and Dietz, R.
Abstract:Background: Statins may improve left ventricular remodeling after myocardial infarction. We tested whether statins inhibit cardiomyocyte apoptosis through glycogen synthase kinase 3{beta} (GSK3{beta}) inactivation and evaluated activation of downstream transcription factors. Methods/results. - Mevastatin and pravastatin activated serine/threonine kinase Akt in neonatal cardiomyocytes dose and time dependently with maximal activation at 15 min/10 μM. 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 2O 2 showed reduced cardiomyocyte apoptosis in the presence of statin. Analysis of signaling pathways downstream of Akt revealed phosphorylation of GSK3{beta}. Transcription factor cAMP-responsive element binding (CREB) protein showed weak phosphorylation at serine 133; transcription factor NF-κB was not significantly activated after statin treatment as evaluated by EMSA. The GSK3{beta} target protein β-catenin was stabilized at 3 h after statin treatment both in neonatal as well as adult rat cardiomyocytes. Transfection with constitutive active GSK3{beta}S9A sensitized neonatal cardiomyocytes to hypoxia/reoxygenation-induced apoptosis as measured by annexin V/propidium iodide staining. Furthermore, myocardial protein extracts of mice revealed GSK3{beta} inactivation after administration of pravastatin intraperitoneally. Conclusions: Statins inhibit cardiomyocyte apoptosis in association with GSK3{beta} inactivation. Inactivation of GSK3{beta} leads to stabilization of {beta} catenin in cardiomyocytes.
Keywords:Apoptosis, {Beta}-Catenin, Cardiomyocyte, Glycogen Synthase Kinase 3{beta}, Hypoxia, Transcription Factor
Source:Journal of Molecular and Cellular Cardiology
ISSN:0022-2828
Publisher:Elsevier (The Netherlands)
Volume:37
Number:3
Page Range:681-690
Date:1 January 2004
Official Publication:https://doi.org/10.1016/j.yjmcc.2004.05.025
PubMed:View item in PubMed

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