Gene remodeling in type 2 diabetic cardiomyopathy and its phenotypic rescue with SERCA2a.

• Main Authors: Ioannis Karakikes, Maengjo Kim, Lahouaria Hadri, Susumu Sakata, Yezhou Sun, Weijia Zhang, Elie R Chemaly, Roger J Hajjar, Djamel Lebeche
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2009-07-01
• Series: PLoS ONE
• Online Access: http://europepmc.org/articles/PMC2714457?pdf=render

BACKGROUND/AIM:Diabetes-associated myocardial dysfunction results in altered gene expression in the heart. We aimed to investigate the changes in gene expression profiles accompanying diabetes-induced cardiomyopathy and its phenotypic rescue by restoration of SERCA2a expression. METHODS/RESULTS:Using the Otsuka Long-Evans Tokushima Fatty rat model of type 2 diabetes and the Agilent rat microarray chip, we analyzed gene expression by comparing differential transcriptional changes in age-matched control versus diabetic hearts and diabetic hearts that received gene transfer of SERCA2a. Microarray expression profiles of selected genes were verified with real-time qPCR and immunoblotting. Our analysis indicates that diabetic cardiomyopathy is associated with a downregulation of transcripts. Diabetic cardiomyopathic hearts have reduced levels of SERCA2a. SERCA2a gene transfer in these hearts reduced diabetes-associated hypertrophy, and differentially modulated the expression of 76 genes and reversed the transcriptional profile induced by diabetes. In isolated cardiomyocytes in vitro, SERCA2a overexpression significantly modified the expression of a number of transcripts known to be involved in insulin signaling, glucose metabolism and cardiac remodeling. CONCLUSION:This investigation provided insight into the pathophysiology of cardiac remodeling and the potential role of SERCA2a normalization in multiple pathways in diabetic cardiomyopathy.