The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy

Ahmet Ucar; Shashi K. Gupta; Jan Fiedler; Erdem Erikci; Michal Kardasinski; Sandor Batkai; Seema Dangwal; Regalla Kumarswamy; Claudia Bang; Angelika Holzmann; Janet Remke; Massimiliano Caprio; Claudia Jentzsch; Stefan Engelhardt; Sabine Geisendorf; Carolina Glas; Thomas G. Hofmann; Michelle Nessling; Karsten Richter; Mario Schiffer; Lucie Carrier; L. Christian Napp; Johann Bauersachs; Kamal Chowdhury; Thomas Thum

doi:10.1038/ncomms2090

The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy

Ahmet Ucar, Shashi K. Gupta, Jan Fiedler, Erdem Erikci, Michal Kardasinski, Sandor Batkai, Seema Dangwal, Regalla Kumarswamy, Claudia Bang, Angelika Holzmann, Janet Remke, Massimiliano Caprio, Claudia Jentzsch, Stefan Engelhardt, Sabine Geisendorf, Carolina Glas, Thomas G. Hofmann, Michelle Nessling, Karsten Richter, Mario SchifferLucie Carrier, L. Christian Napp, Johann Bauersachs, Kamal Chowdhury, Thomas Thum

Istituto San Raffaele Pisana

Research output: Contribution to journal › Article › peer-review

Abstract

Pathological growth of cardiomyocytes (hypertrophy) is a major determinant for the development of heart failure, one of the leading medical causes of mortality worldwide. Here we show that the microRNA (miRNA)-212/132 family regulates cardiac hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli upregulate cardiomyocyte expression of miR-212 and miR-132, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload- induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and death in mice. Both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and an impaired autophagic response upon starvation. Pharmacological inhibition of miR-132 by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.

Original language	English
Article number	1078
Journal	Nature Communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms2090
Publication status	Published - 2012

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Chemistry(all)
Physics and Astronomy(all)

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10.1038/ncomms2090

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Ucar, A., Gupta, S. K., Fiedler, J., Erikci, E., Kardasinski, M., Batkai, S., Dangwal, S., Kumarswamy, R., Bang, C., Holzmann, A., Remke, J., Caprio, M., Jentzsch, C., Engelhardt, S., Geisendorf, S., Glas, C., Hofmann, T. G., Nessling, M., Richter, K., ... Thum, T. (2012). The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nature Communications, 3, [1078]. https://doi.org/10.1038/ncomms2090

Ucar, A, Gupta, SK, Fiedler, J, Erikci, E, Kardasinski, M, Batkai, S, Dangwal, S, Kumarswamy, R, Bang, C, Holzmann, A, Remke, J, Caprio, M, Jentzsch, C, Engelhardt, S, Geisendorf, S, Glas, C, Hofmann, TG, Nessling, M, Richter, K, Schiffer, M, Carrier, L, Napp, LC, Bauersachs, J, Chowdhury, K & Thum, T 2012, 'The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy', Nature Communications, vol. 3, 1078. https://doi.org/10.1038/ncomms2090

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title = "The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy",

abstract = "Pathological growth of cardiomyocytes (hypertrophy) is a major determinant for the development of heart failure, one of the leading medical causes of mortality worldwide. Here we show that the microRNA (miRNA)-212/132 family regulates cardiac hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli upregulate cardiomyocyte expression of miR-212 and miR-132, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload- induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and death in mice. Both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and an impaired autophagic response upon starvation. Pharmacological inhibition of miR-132 by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.",

author = "Ahmet Ucar and Gupta, {Shashi K.} and Jan Fiedler and Erdem Erikci and Michal Kardasinski and Sandor Batkai and Seema Dangwal and Regalla Kumarswamy and Claudia Bang and Angelika Holzmann and Janet Remke and Massimiliano Caprio and Claudia Jentzsch and Stefan Engelhardt and Sabine Geisendorf and Carolina Glas and Hofmann, {Thomas G.} and Michelle Nessling and Karsten Richter and Mario Schiffer and Lucie Carrier and Napp, {L. Christian} and Johann Bauersachs and Kamal Chowdhury and Thomas Thum",

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AU - Ucar, Ahmet

AU - Gupta, Shashi K.

AU - Fiedler, Jan

AU - Erikci, Erdem

AU - Kardasinski, Michal

AU - Batkai, Sandor

AU - Dangwal, Seema

AU - Kumarswamy, Regalla

AU - Bang, Claudia

AU - Holzmann, Angelika

AU - Remke, Janet

AU - Caprio, Massimiliano

AU - Jentzsch, Claudia

AU - Engelhardt, Stefan

AU - Geisendorf, Sabine

AU - Glas, Carolina

AU - Hofmann, Thomas G.

AU - Nessling, Michelle

AU - Richter, Karsten

AU - Schiffer, Mario

AU - Carrier, Lucie

AU - Napp, L. Christian

AU - Bauersachs, Johann

AU - Chowdhury, Kamal

AU - Thum, Thomas

PY - 2012

Y1 - 2012

N2 - Pathological growth of cardiomyocytes (hypertrophy) is a major determinant for the development of heart failure, one of the leading medical causes of mortality worldwide. Here we show that the microRNA (miRNA)-212/132 family regulates cardiac hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli upregulate cardiomyocyte expression of miR-212 and miR-132, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload- induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and death in mice. Both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and an impaired autophagic response upon starvation. Pharmacological inhibition of miR-132 by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.

AB - Pathological growth of cardiomyocytes (hypertrophy) is a major determinant for the development of heart failure, one of the leading medical causes of mortality worldwide. Here we show that the microRNA (miRNA)-212/132 family regulates cardiac hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli upregulate cardiomyocyte expression of miR-212 and miR-132, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload- induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and death in mice. Both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and an impaired autophagic response upon starvation. Pharmacological inhibition of miR-132 by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.

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The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy

Abstract

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