MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts.
BACKGROUND
MicroRNA (miR)-133a regulates cardiac and skeletal muscle differentiation and plays an important role in cardiac development. Because miR-133a levels decrease during reactive cardiac hypertrophy, some have considered that restoring miR-133a levels could suppress hypertrophic remodeling.


OBJECTIVE
To prevent the "normal" downregulation of miR-133a induced by an acute hypertrophic stimulus in the adult heart.


RESULTS
miR-133a is downregulated in transverse aortic constriction (TAC) and isoproterenol-induced hypertrophy, but not in 2 genetic hypertrophy models. Using MYH6 promoter-directed expression of a miR-133a genomic precursor, increased cardiomyocyte miR-133a had no effect on postnatal cardiac development assessed by measures of structure, function, and mRNA profile. However, increased miR-133a levels increased QT intervals in surface electrocardiographic recordings and action potential durations in isolated ventricular myocytes, with a decrease in the fast component of the transient outward K+ current, I(to,f), at baseline. Transgenic expression of miR-133a prevented TAC-associated miR-133a downregulation and improved myocardial fibrosis and diastolic function without affecting the extent of hypertrophy. I(to,f) downregulation normally observed post-TAC was prevented in miR-133a transgenic mice, although action potential duration and QT intervals did not reflect this benefit. miR-133a transgenic hearts had no significant alterations of basal or post-TAC mRNA expression profiles, although decreased mRNA and protein levels were observed for the I(to,f) auxiliary KChIP2 subunit, which is not a predicted target.


CONCLUSIONS
These results reveal striking differences between in vitro and in vivo phenotypes of miR expression, and further suggest that mRNA signatures do not reliably predict either direct miR targets or major miR effects.
Matkovich
Scot J
SJ
Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Wang
Wei
W
Tu
Yizheng
Y
Eschenbacher
William H
WH
Dorn
Lisa E
LE
Condorelli
Gianluigi
G
Diwan
Abhinav
A
Nerbonne
Jeanne M
JM
Dorn
Gerald W
GW
D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology; D003971:Diastole; D004562:Electrocardiography; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000235:genetics; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol / Q000009:adverse effects / Q000494:pharmacology; D051605:Kv Channel-Interacting Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics
D002316:Cardiotonic Agents; C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D018995:Myosin Heavy Chains; D007545:Isoproterenol