miR133a regulates cardiomyocyte hypertrophy in diabetes.
BACKGROUND
Diabetic cardiomyopathy, characterized by cardiac hypertrophy and contractile dysfunction, eventually leads to heart failure. We have previously shown that alterations of a number of key molecules are involved in producing cardiomyocyte hypertrophy in diabetes. The aim of the present study was to determine whether microRNAs (miRNA) play a role in mediating altered gene expression and structural/functional deficits in the heart in diabetes.


METHODS
STZ-induced diabetic mice were haemodynamically investigated after 2 months of diabetes to establish the development of cardiomyopathy. The tissues were then examined for gene expression and microRNA analysis. We further investigated neonatal rat cardiomyocytes to identify the mechanisms of glucose-induced hypertrophy and the potential role of miR133a.


RESULTS
Diabetic mice showed myocardial contractile dysfunction and augmented mRNA expression of atrial and brain natriuretic peptides (ANP, BNP), MEF2A and MEF2C, SGK1 and IGF1R compared to age- and sex-matched controls. Cardiac tissues from these mice showed alteration of multiple miRNAs by array analysis including miR133a, which was confirmed by RT-PCR. In vitro exposure of cardiomyocytes to high levels of glucose produced hypertrophic changes and reduced expression of miRNA133a. Finally, transfection of miR133a mimics prevented altered gene expression and hypertrophic changes.


CONCLUSIONS
Data from these studies demonstrate a novel glucose-induced mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes which is mediated through miR133a.
Feng
Biao
B
Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Chen
Shali
S
George
Biju
B
Feng
Qingping
Q
Chakrabarti
Subrata
S
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology*; D018929:Cell Culture Techniques; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000235:genetics / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000166:cytology; D006439:Hemodynamics; D026161:MADS Domain Proteins / Q000235:genetics; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D032342:Muscle Cells / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D018006:Myogenic Regulatory Factors / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578037:MEF2A protein, rat; C578042:MEF2C protein, rat; D035683:MicroRNAs; D018006:Myogenic Regulatory Factors