Abstract
Growing evidence indicates that microRNAs (miRNAs or miRs) are involved in basic cell functions and oncogenesis. Here we report that miR-133 has a critical role in determining cardiomyocyte hypertrophy. We observed decreased expression of both miR-133 and miR-1, which belong to the same transcriptional unit, in mouse and human models of cardiac hypertrophy. In vitro overexpression of miR-133 or miR-1 inhibited cardiac hypertrophy. In contrast, suppression of miR-133 by 'decoy' sequences induced hypertrophy, which was more pronounced than that after stimulation with conventional inducers of hypertrophy. In vivo inhibition of miR-133 by a single infusion of an antagomir caused marked and sustained cardiac hypertrophy. We identified specific targets of miR-133: RhoA, a GDP-GTP exchange protein regulating cardiac hypertrophy; Cdc42, a signal transduction kinase implicated in hypertrophy; and Nelf-A/WHSC2, a nuclear factor involved in cardiogenesis. Our data show that miR-133, and possibly miR-1, are key regulators of cardiac hypertrophy, suggesting their therapeutic application in heart disease.
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Acknowledgements
We thank M. Blasi, M. Fontana and V. Michetti for editorial assistance, and G. Loreto for graphics. This work was supported by grants from the US National Institutes of Health (HL078797-01A1 to G.C., HLO65484 to P.R.-L. and 1R01HL63168 to C.P.), the Marie Curie Outgoing Fellowship 6th European Framework Programme (D.C.), EUGeneHeart (LSHM-CT-2005-018833 to G.C.), the Italian Ministry of Scientific Research (G.C. and C.P.), the Italian Ministry of Health (C.P. and G.C.) and the Italy-USA miR Oncology Program, Istituto Superiore di Sanità, Rome (C.P.).
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D.C., A.C., D.B., F.F., A.A., M.V.G.L., P.S., M.-L.B. and L.E. conducted the in vitro and in vivo experiments. D.C. and P.R-L. performed the assessment of miRNAs in mouse cardiac development. P.G., Y.G., N.D.D., G.W.D., Ø.E. and K.L.P. performed the in vivo models of cardiac hypertrophy. C.A. and M.A.R. collected human samples. C.M.C. conducted the miRNA microarray analysis. A.C., D.C., C.P. and G.C. planned the experiments. D.C., A.C., M.-L.B., P.R.-L., C.P. and G.C. wrote the manuscript. C.P. and G.C. were responsible for research coordination and strategy.
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Supplementary information
Supplementary Fig. 1
MiR-133 and miR-1 expression in fetal and adult tissues. (PDF 335 kb)
Supplementary Fig. 2
MiR-1 expression in cardiac hypertrophy. (PDF 1273 kb)
Supplementary Fig. 3
Morphological analysis of mock, Ad133 or AdDecoy infected adult CMs. (PDF 239 kb)
Supplementary Fig. 4
In vivo effects of AdDecoy and Ad133 on cardiac hypertrophy. (PDF 101 kb)
Supplementary Fig. 5
Identification of miR-133 target genes: RhoA and Cdc42. (PDF 126 kb)
Supplementary Fig. 6
Identification of miR-133 target genes: Nelf-A/WHSC2. (PDF 760 kb)
Supplementary Table 1
Echocardiographic assessment in wt and Akt Tg mice in basal condition and after pressure overload stimuli (PDF 21 kb)
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Carè, A., Catalucci, D., Felicetti, F. et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med 13, 613–618 (2007). https://doi.org/10.1038/nm1582
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DOI: https://doi.org/10.1038/nm1582
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