Publication Date:
2014-03-29
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131725/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131725/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wahlquist, Christine -- Jeong, Dongtak -- Rojas-Munoz, Agustin -- Kho, Changwon -- Lee, Ahyoung -- Mitsuyama, Shinichi -- van Mil, Alain -- Park, Woo Jin -- Sluijter, Joost P G -- Doevendans, Pieter A F -- Hajjar, Roger J -- Mercola, Mark -- HHSN268201000045C/HL/NHLBI NIH HHS/ -- HHSN26820100045C/PHS HHS/ -- P01 HL098053/HL/NHLBI NIH HHS/ -- P01HL098053/HL/NHLBI NIH HHS/ -- P20 HL100396/HL/NHLBI NIH HHS/ -- P20HL100396/HL/NHLBI NIH HHS/ -- P30 AR061303/AR/NIAMS NIH HHS/ -- P30 CA030199/CA/NCI NIH HHS/ -- P30AR061303/AR/NIAMS NIH HHS/ -- P30CA030199/CA/NCI NIH HHS/ -- P50 HL112324/HL/NHLBI NIH HHS/ -- P50HL112324/HL/NHLBI NIH HHS/ -- R01 HL088434/HL/NHLBI NIH HHS/ -- R01 HL093183/HL/NHLBI NIH HHS/ -- R01 HL108176/HL/NHLBI NIH HHS/ -- R01 HL113601/HL/NHLBI NIH HHS/ -- R01HL088434/HL/NHLBI NIH HHS/ -- R01HL093183/HL/NHLBI NIH HHS/ -- R01HL108176/HL/NHLBI NIH HHS/ -- R01HL113601/HL/NHLBI NIH HHS/ -- S10 RR021084/RR/NCRR NIH HHS/ -- England -- Nature. 2014 Apr 24;508(7497):531-5. doi: 10.1038/nature13073. Epub 2014 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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]. ; 1] The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2]. ; 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. ; The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; 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. ; Global Research Laboratory, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, South Korea. ; Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670661" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Calcium/metabolism
;
Dependovirus/genetics
;
Disease Models, Animal
;
HEK293 Cells
;
Heart/drug effects/physiology/physiopathology
;
Heart Failure/*genetics/*therapy
;
Humans
;
Kinetics
;
Male
;
Mice
;
MicroRNAs/analysis/*antagonists & inhibitors/genetics/metabolism
;
Myocardial Contraction/*drug effects
;
Myocardium/metabolism
;
Myocytes, Cardiac/metabolism
;
Oligonucleotides, Antisense/genetics/metabolism/pharmacology
;
RNA, Messenger/genetics/metabolism
;
Sarcoplasmic Reticulum/metabolism
;
Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism
;
Survival Analysis
;
Up-Regulation/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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