TY - JOUR
T1 - Inhibition of miR-25 improves cardiac contractility in the failing heart
AU - Wahlquist, Christine
AU - Jeong, Dongtak
AU - Rojas-Muñoz, Agustin
AU - Kho, Changwon
AU - Lee, Ahyoung
AU - Mitsuyama, Shinichi
AU - Van Mil, Alain
AU - Jin Park, Woo
AU - Sluijter, Joost P.G.
AU - Doevendans, Pieter A.F.
AU - Hajjar, Roger J.
AU - Mercola, Mark
N1 - Funding Information:
Acknowledgements We thank P. Aza-Blanc and F. Cerignoli; O. Kim, L. Liang and E. Kohlbrenner for their technical support; G. Christensen for providing the SERCA2a knockout mice; and H. el Azzouzi for TAC operations and histological sections. This work was supported by California Institute for Regenerative Medicine (RC1-000132), the National Institutes of Health (NIH) (R01HL113601, P01HL098053 and R01HL108176) and the Fondation Leducq to M.M.; by the NIH (NIH R01HL093183, R01HL088434, P20HL100396 and a Program of Excellence in Nanotechnology Contract no. HHSN26820100045C and P50HL112324) to R.J.H.; P30CA030199 and P30AR061303 for Sanford-Burnham Medical Research Institute functional genomics and cytometry. W.J.P.wassupportedbythe GlobalResearchLaboratory Programofthe South Korean Government (M6-0605-00-0001). J.P.G.S. and P.A.F.D. were supported by the Netherlands Heart foundation and Project P1.05 LUST of the BioMedical Materials institute co-fundedbytheDutchMinistry ofEconomicAffairs,Agricultureand Innovation. C.W. was supported by a fellowship from the Spanish National Research Council. A.v.M. was a Netherlands Heart Institute ICIN fellow.
PY - 2014
Y1 - 2014
N2 - Heart failure is characterized by a debilitating decline in cardiac function, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy. MicroRNAs (miRNAs) are dysregulated in heart failure but whether they control contractility or constitute therapeutic targets remains speculative. Using high-throughput functional screening of the human microRNAome, here we identify miRNAs that suppress intracellular calcium handling in heart muscle by interacting with messenger RNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a (also known as ATP2A2). Of 875 miRNAs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas adeno-associated virus 9 (AAV9)-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 markedly halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR oligonucleotide. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggest that it might be targeted therapeutically to restore function.
AB - Heart failure is characterized by a debilitating decline in cardiac function, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy. MicroRNAs (miRNAs) are dysregulated in heart failure but whether they control contractility or constitute therapeutic targets remains speculative. Using high-throughput functional screening of the human microRNAome, here we identify miRNAs that suppress intracellular calcium handling in heart muscle by interacting with messenger RNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a (also known as ATP2A2). Of 875 miRNAs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas adeno-associated virus 9 (AAV9)-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 markedly halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR oligonucleotide. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggest that it might be targeted therapeutically to restore function.
UR - http://www.scopus.com/inward/record.url?scp=84899482237&partnerID=8YFLogxK
U2 - 10.1038/nature13073
DO - 10.1038/nature13073
M3 - Article
C2 - 24670661
AN - SCOPUS:84899482237
SN - 0028-0836
VL - 508
SP - 531
EP - 535
JO - Nature
JF - Nature
IS - 7497
ER -