TY - JOUR
T1 - MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts
AU - Matkovich, Scot J.
AU - Wang, Wei
AU - Tu, Yizheng
AU - Eschenbacher, William H.
AU - Dorn, Lisa E.
AU - Condorelli, Gianluigi
AU - Diwan, Abhinav
AU - Nerbonne, Jeanne M.
AU - Dorn, Gerald W.
PY - 2010
Y1 - 2010
N2 - RATIONALE: 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. METHODS AND 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.
AB - RATIONALE: 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. METHODS AND 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.
KW - Apoptosis
KW - Cardiac channels
KW - Cardiac hypertrophy
KW - MicroRNA
KW - Myocardial fibrosis
UR - http://www.scopus.com/inward/record.url?scp=74049096307&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.109.202176
DO - 10.1161/CIRCRESAHA.109.202176
M3 - Article
C2 - 19893015
AN - SCOPUS:74049096307
SN - 0009-7330
VL - 106
SP - 166
EP - 175
JO - Circulation research
JF - Circulation research
IS - 1
ER -