title: Inhibition of miR-25 improves cardiac contractility in the failing heart.
abstract: 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.
authors.affiliation: 1] Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [2].
authors.forename: Christine
authors.initials: C
authors.lastname: Wahlquist
authors.affiliation: 1] The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2].
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.affiliation: Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Agustin
authors.initials: A
authors.lastname: Rojas-Muñoz
authors.affiliation: The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Changwon
authors.initials: C
authors.lastname: Kho
authors.affiliation: The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Ahyoung
authors.initials: A
authors.lastname: Lee
authors.affiliation: The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mitsuyama
authors.affiliation: 1] Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [2] Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands.
authors.forename: Alain
authors.initials: A
authors.lastname: van Mil
authors.affiliation: Global Research Laboratory, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, South Korea.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.affiliation: Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands.
authors.forename: Joost P G
authors.initials: JP
authors.lastname: Sluijter
authors.affiliation: Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands.
authors.forename: Pieter A F
authors.initials: PA
authors.lastname: Doevendans
authors.affiliation: The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D015854:Up-Regulation / Q000235:genetics
chemical_list: C543351:MIRN25 microRNA, human; C558895:MIRN25 microRNA, mouse; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium