miR-206 Mediates YAP-Induced Cardiac Hypertrophy and Survival.
BACKGROUND
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.


OBJECTIVE
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.


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.
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Yanfei
Y
Yang
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Dominic P
DP
Del Re
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Noritsugu
N
Nakano
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Sebastiano
S
Sciarretta
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Peiyong
P
Zhai
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Jiyeon
J
Park
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Danish
D
Sayed
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Akihiro
A
Shirakabe
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Shoji
S
Matsushima
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Yongkyu
Y
Park
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Bin
B
Tian
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Maha
M
Abdellatif
From the Cardiovascular Research Institute and the Department of Cell Biology and Molecular Medicine (Y.Y., D.P.D.R., N.N., P.Z., D.S., A.S., S.M., Y.P., M.A., J.S.), and Department of Biochemistry (J.P., B.T.), Rutgers, New Jersey Medical School, Newark; and the Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Latina and IRCCS Neuromed, Pozzilli (IS), Italy (S.S.).
Junichi
J
Sadoshima
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D020257:Ventricular Remodeling; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; C561586:FoxP1 protein, rat; C432917:Foxp1 protein, mouse; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; D010750:Phosphoproteins; D012097:Repressor Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C509425:Yap1 protein, rat; C522220:mirn206 microRNA, rat
apoptosis; heart; hypertrophy; microRNAs; signal transduction