MIR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival

Yanfei Yang, Dominic P. Del Re, Noritsugu Nakano, Sebastiano Sciarretta, Peiyong Zhai, Jiyeon Park, Danish Sayed, Akihiro Shirakabe, Shoji Matsushima, Yongkyu Park, Bin Tian, Maha Abdellatif, Junichi Sadoshima

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Rationale: In Drosophila, the Hippo signaling pathway negatively regulates organ size by suppressing cell proliferation and survival through the inhibition of Yorkie, a transcriptional cofactor. Yes-associated protein (YAP), the mammalian homolog of Yorkie, promotes cardiomyocyte growth and survival in postnatal hearts. However, the underlying mechanism responsible for the beneficial effect of YAP in cardiomyocytes remains unclear. Objectives: We investigated whether miR-206, a microRNA known to promote hypertrophy in skeletal muscle, mediates the effect of YAP on promotion of survival and hypertrophy in cardiomyocytes. Methods and Results: Microarray analysis indicated that YAP increased miR-206 expression in cardiomyocytes. Increased miR-206 expression induced cardiac hypertrophy and inhibited cell death in cultured cardiomyocytes, similar to that of YAP. Downregulation of endogenous miR-206 in cardiomyocytes attenuated YAP-induced cardiac hypertrophy and survival, suggesting that miR-206 plays a critical role in mediating YAP function. Cardiac-specific overexpression of miR-206 in mice induced hypertrophy and protected the heart from ischemia/reperfusion injury, whereas suppression of miR-206 exacerbated ischemia/reperfusion injury and prevented pressure overload-induced cardiac hypertrophy. miR-206 negatively regulates Forkhead box protein P1 expression in cardiomyocytes and overexpression of Forkhead box protein P1 attenuated miR-206-induced cardiac hypertrophy and survival, suggesting that Forkhead box protein P1 is a functional target of miR-206. Conclusions: YAP increases the abundance of miR-206, which in turn plays an essential role in mediating hypertrophy and survival by silencing Forkhead box protein P1 in cardiomyocytes.

Original languageEnglish
Pages (from-to)891-904
Number of pages14
JournalCirculation research
Volume117
Issue number10
DOIs
Publication statusPublished - Oct 23 2015

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Cardiomegaly
Cardiac Myocytes
Forkhead Transcription Factors
Proteins
Hypertrophy
Reperfusion Injury
Organ Size
Microarray Analysis
MicroRNAs
Drosophila
Cell Survival
Skeletal Muscle
Cell Death
Down-Regulation
Cell Proliferation
Pressure
Growth

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Yang, Y., Del Re, D. P., Nakano, N., Sciarretta, S., Zhai, P., Park, J., ... Sadoshima, J. (2015). MIR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival. Circulation research, 117(10), 891-904. https://doi.org/10.1161/CIRCRESAHA.115.306624

MIR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival. / Yang, Yanfei; Del Re, Dominic P.; Nakano, Noritsugu; Sciarretta, Sebastiano; Zhai, Peiyong; Park, Jiyeon; Sayed, Danish; Shirakabe, Akihiro; Matsushima, Shoji; Park, Yongkyu; Tian, Bin; Abdellatif, Maha; Sadoshima, Junichi.

In: Circulation research, Vol. 117, No. 10, 23.10.2015, p. 891-904.

Research output: Contribution to journalArticle

Yang, Y, Del Re, DP, Nakano, N, Sciarretta, S, Zhai, P, Park, J, Sayed, D, Shirakabe, A, Matsushima, S, Park, Y, Tian, B, Abdellatif, M & Sadoshima, J 2015, 'MIR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival', Circulation research, vol. 117, no. 10, pp. 891-904. https://doi.org/10.1161/CIRCRESAHA.115.306624
Yang Y, Del Re DP, Nakano N, Sciarretta S, Zhai P, Park J et al. MIR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival. Circulation research. 2015 Oct 23;117(10):891-904. https://doi.org/10.1161/CIRCRESAHA.115.306624
Yang, Yanfei ; Del Re, Dominic P. ; Nakano, Noritsugu ; Sciarretta, Sebastiano ; Zhai, Peiyong ; Park, Jiyeon ; Sayed, Danish ; Shirakabe, Akihiro ; Matsushima, Shoji ; Park, Yongkyu ; Tian, Bin ; Abdellatif, Maha ; Sadoshima, Junichi. / MIR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival. In: Circulation research. 2015 ; Vol. 117, No. 10. pp. 891-904.
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AU - Del Re, Dominic P.

AU - Nakano, Noritsugu

AU - Sciarretta, Sebastiano

AU - Zhai, Peiyong

AU - Park, Jiyeon

AU - Sayed, Danish

AU - Shirakabe, Akihiro

AU - Matsushima, Shoji

AU - Park, Yongkyu

AU - Tian, Bin

AU - Abdellatif, Maha

AU - Sadoshima, Junichi

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N2 - Rationale: In Drosophila, the Hippo signaling pathway negatively regulates organ size by suppressing cell proliferation and survival through the inhibition of Yorkie, a transcriptional cofactor. Yes-associated protein (YAP), the mammalian homolog of Yorkie, promotes cardiomyocyte growth and survival in postnatal hearts. However, the underlying mechanism responsible for the beneficial effect of YAP in cardiomyocytes remains unclear. Objectives: We investigated whether miR-206, a microRNA known to promote hypertrophy in skeletal muscle, mediates the effect of YAP on promotion of survival and hypertrophy in cardiomyocytes. Methods and Results: Microarray analysis indicated that YAP increased miR-206 expression in cardiomyocytes. Increased miR-206 expression induced cardiac hypertrophy and inhibited cell death in cultured cardiomyocytes, similar to that of YAP. Downregulation of endogenous miR-206 in cardiomyocytes attenuated YAP-induced cardiac hypertrophy and survival, suggesting that miR-206 plays a critical role in mediating YAP function. Cardiac-specific overexpression of miR-206 in mice induced hypertrophy and protected the heart from ischemia/reperfusion injury, whereas suppression of miR-206 exacerbated ischemia/reperfusion injury and prevented pressure overload-induced cardiac hypertrophy. miR-206 negatively regulates Forkhead box protein P1 expression in cardiomyocytes and overexpression of Forkhead box protein P1 attenuated miR-206-induced cardiac hypertrophy and survival, suggesting that Forkhead box protein P1 is a functional target of miR-206. Conclusions: YAP increases the abundance of miR-206, which in turn plays an essential role in mediating hypertrophy and survival by silencing Forkhead box protein P1 in cardiomyocytes.

AB - Rationale: In Drosophila, the Hippo signaling pathway negatively regulates organ size by suppressing cell proliferation and survival through the inhibition of Yorkie, a transcriptional cofactor. Yes-associated protein (YAP), the mammalian homolog of Yorkie, promotes cardiomyocyte growth and survival in postnatal hearts. However, the underlying mechanism responsible for the beneficial effect of YAP in cardiomyocytes remains unclear. Objectives: We investigated whether miR-206, a microRNA known to promote hypertrophy in skeletal muscle, mediates the effect of YAP on promotion of survival and hypertrophy in cardiomyocytes. Methods and Results: Microarray analysis indicated that YAP increased miR-206 expression in cardiomyocytes. Increased miR-206 expression induced cardiac hypertrophy and inhibited cell death in cultured cardiomyocytes, similar to that of YAP. Downregulation of endogenous miR-206 in cardiomyocytes attenuated YAP-induced cardiac hypertrophy and survival, suggesting that miR-206 plays a critical role in mediating YAP function. Cardiac-specific overexpression of miR-206 in mice induced hypertrophy and protected the heart from ischemia/reperfusion injury, whereas suppression of miR-206 exacerbated ischemia/reperfusion injury and prevented pressure overload-induced cardiac hypertrophy. miR-206 negatively regulates Forkhead box protein P1 expression in cardiomyocytes and overexpression of Forkhead box protein P1 attenuated miR-206-induced cardiac hypertrophy and survival, suggesting that Forkhead box protein P1 is a functional target of miR-206. Conclusions: YAP increases the abundance of miR-206, which in turn plays an essential role in mediating hypertrophy and survival by silencing Forkhead box protein P1 in cardiomyocytes.

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