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


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.


CONCLUSIONS
This investigation provided insight into the pathophysiology of cardiac remodeling and the potential role of SERCA2a normalization in multiple pathways in diabetic cardiomyopathy.
Karakikes
Ioannis
I
Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York, United States of America.
Kim
Maengjo
M
Hadri
Lahouaria
L
Sakata
Susumu
S
Sun
Yezhou
Y
Zhang
Weijia
W
Chemaly
Elie R
ER
Hajjar
Roger J
RJ
Lebeche
Djamel
D
D000818:Animals; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D020869:Gene Expression Profiling; D006331:Heart Diseases / Q000150:complications / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051381:Rats; D020318:Rats, Long-Evans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases