Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat

Cardiovascular Diabetology

Original Investigation

Ilkka Tikkanen¹  Hanna Forstén¹  Ville Kytö²  Marjut Louhelainen³  Saara Merasto³  Johanna Raivio³  Petri Kaheinen³  Erik Vahtola³  Eero Mervaala³  Jouko Levijoki⁴ 

[1] Department of Medicine, Helsinki University Hospital, Finland and Minerva Institute for Medical Research, Helsinki, Finland;Department of Medicine, Turku University Hospital, Turku, Finland;Institute of Biomedicine, Pharmacology, University of Helsinki, Finland;Orion Pharma Ltd, Espoo, Finland;

关键词: Atrial Natriuretic Peptide;    Connective Tissue Growth Factor;    Electrophoretic Mobility Shift Assay;    Cardiomyocyte Apoptosis;    Cardiomyocyte Hypertrophy;   

DOI  :  10.1186/1475-2840-9-5

 received in 2009-11-10, accepted in 2010-01-27,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundDiabetes is associated with changes in myocardial stress-response pathways and is recognized as an independent risk factor for cardiac remodeling. Using spontaneously diabetic Goto Kakizaki rats as a model of type 2 DM we investigated whether post-translational modifications in the Akt - FOXO3a pathway, Sirt1 - p53 pathway and the mitogen activated protein kinase p38 regulator are involved in post-infarct cardiac remodelingMethodsExperimental myocardial infarction (MI) was induced by left anterior descending coronary artery ligation in spontaneously diabetic Goto-Kakizaki rats and non-diabetic Wistar controls. Cardiac function was studied by echocardiography. Myocardial hypertrophy, cardiomyocyte apoptosis and cardiac fibrosis were determined histologically 12 weeks post MI or Sham operation. Western blotting was used to study Caspase-3, Bax, Sirt1, acetylation of p53 and phosphorylation of p38, Akt and FOXO3a. Electrophoretic mobility shift assay was used to assess FOXO3a activity and its nuclear localization.ResultsPost-infarct heart failure in diabetic GK rats was associated with pronounced cardiomyocyte hypertrophy, increased interstitial fibrosis and sustained cardiomyocyte apoptosis as compared with their non-diabetic Wistar controls. In the GK rat myocardium, Akt- and FOXO3a-phosphorylation was decreased and nuclear localization of FOXO3a was increased concomitantly with increased PTEN protein expression. Furthermore, increased Sirt1 protein expression was associated with decreased p53 acetylation, and phosphorylation of p38 was increased in diabetic rats with MI.ConclusionsPost-infarct heart failure in diabetic GK rats was associated with more pronounced cardiac hypertrophy, interstitial fibrosis and sustained cardiomyocyte apoptosis as compared to their non-diabetic controls. The present study suggests important roles for Akt-FOXO3a, Sirt1 - p53 and p38 MAPK in the regulation of post-infarct cardiac remodeling in type 2 diabetes.

【 授权许可】

Unknown   
© Vahtola et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.