PMID- 24670661 OWN - NLM STAT- MEDLINE DCOM- 20140813 LR - 20220408 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 508 IP - 7497 DP - 2014 Apr 24 TI - Inhibition of miR-25 improves cardiac contractility in the failing heart. PG - 531-5 LID - 10.1038/nature13073 [doi] 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. FAU - Wahlquist, Christine AU - Wahlquist C AD - 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]. FAU - Jeong, Dongtak AU - Jeong D AD - 1] The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2]. FAU - Rojas-Munoz, Agustin AU - Rojas-Munoz A AD - 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. FAU - Kho, Changwon AU - Kho C AD - The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. FAU - Lee, Ahyoung AU - Lee A AD - The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. FAU - Mitsuyama, Shinichi AU - Mitsuyama S AD - The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. FAU - van Mil, Alain AU - van Mil A AD - 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. FAU - Park, Woo Jin AU - Park WJ AD - Global Research Laboratory, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, South Korea. FAU - Sluijter, Joost P G AU - Sluijter JP AD - Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands. FAU - Doevendans, Pieter A F AU - Doevendans PA AD - Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands. FAU - Hajjar, Roger J AU - Hajjar RJ AD - The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. FAU - Mercola, Mark AU - Mercola M AD - 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. LA - eng GR - P01HL098053/HL/NHLBI NIH HHS/United States GR - HHSN268201000045C/HL/NHLBI NIH HHS/United States GR - R01HL093183/HL/NHLBI NIH HHS/United States GR - R01 HL088434/HL/NHLBI NIH HHS/United States GR - R01 HL113601/HL/NHLBI NIH HHS/United States GR - R01HL088434/HL/NHLBI NIH HHS/United States GR - HHSN26820100045C/PHS HHS/United States GR - K99 HL116645/HL/NHLBI NIH HHS/United States GR - P30 AR061303/AR/NIAMS NIH HHS/United States GR - P50 HL112324/HL/NHLBI NIH HHS/United States GR - P30CA030199/CA/NCI NIH HHS/United States GR - P30 CA030199/CA/NCI NIH HHS/United States GR - P20HL100396/HL/NHLBI NIH HHS/United States GR - P30AR061303/AR/NIAMS NIH HHS/United States GR - P20 HL100396/HL/NHLBI NIH HHS/United States GR - R01 HL108176/HL/NHLBI NIH HHS/United States GR - R01HL113601/HL/NHLBI NIH HHS/United States GR - P50HL112324/HL/NHLBI NIH HHS/United States GR - S10 RR021084/RR/NCRR NIH HHS/United States GR - R01HL108176/HL/NHLBI NIH HHS/United States GR - P01 HL098053/HL/NHLBI NIH HHS/United States GR - R01 HL093183/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140312 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (MIRN25 microRNA, human) RN - 0 (MIRN25 microRNA, mouse) RN - 0 (MicroRNAs) RN - 0 (Oligonucleotides, Antisense) RN - 0 (RNA, Messenger) RN - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases) RN - SY7Q814VUP (Calcium) SB - IM CIN - Nat Rev Drug Discov. 2014 May;13(5):336. PMID: 24781545 CIN - Cell Metab. 2014 Jun 3;19(6):896-7. PMID: 24896535 CIN - Circ Cardiovasc Genet. 2014 Jun;7(3):393-4. PMID: 24951666 CIN - Circ Res. 2014 Sep 12;115(7):610-2. PMID: 25214573 MH - Animals MH - Calcium/metabolism MH - Dependovirus/genetics MH - Disease Models, Animal MH - HEK293 Cells MH - Heart/drug effects/physiology/physiopathology MH - Heart Failure/*genetics/*therapy MH - Humans MH - Kinetics MH - Male MH - Mice MH - MicroRNAs/analysis/*antagonists & inhibitors/genetics/metabolism MH - Myocardial Contraction/*drug effects MH - Myocardium/metabolism MH - Myocytes, Cardiac/metabolism MH - Oligonucleotides, Antisense/genetics/metabolism/pharmacology MH - RNA, Messenger/genetics/metabolism MH - Sarcoplasmic Reticulum/metabolism MH - Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism MH - Survival Analysis MH - Up-Regulation/genetics PMC - PMC4131725 MID - NIHMS559587 EDAT- 2014/03/29 06:00 MHDA- 2014/08/15 06:00 PMCR- 2014/10/24 CRDT- 2014/03/28 06:00 PHST- 2013/01/01 00:00 [received] PHST- 2014/01/23 00:00 [accepted] PHST- 2014/03/28 06:00 [entrez] PHST- 2014/03/29 06:00 [pubmed] PHST- 2014/08/15 06:00 [medline] PHST- 2014/10/24 00:00 [pmc-release] AID - nature13073 [pii] AID - 10.1038/nature13073 [doi] PST - ppublish SO - Nature. 2014 Apr 24;508(7497):531-5. doi: 10.1038/nature13073. Epub 2014 Mar 12.