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In vivo suppression of microRNA-24 prevents the transition toward decompensated hypertrophy in aortic-constricted mice.
- Source :
-
Circulation research [Circ Res] 2013 Feb 15; Vol. 112 (4), pp. 601-5. Date of Electronic Publication: 2013 Jan 10. - Publication Year :
- 2013
-
Abstract
- Rationale: During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca(2+) channels in the cell membrane/T-tubules and ryanodine receptors in the sarcoplasmic reticulum becomes defective, partially because of the decreased expression of a T-tubule-sarcoplasmic reticulum anchoring protein, junctophilin-2. MicroRNA (miR)-24, a junctophilin-2 suppressing miR, is upregulated in hypertrophied and failing cardiomyocytes.<br />Objective: To test whether miR-24 suppression can protect the structural and functional integrity of L-type Ca(2+) channel-ryanodine receptor signaling in hypertrophied cardiomyocytes.<br />Methods and Results: In vivo silencing of miR-24 by a specific antagomir in an aorta-constricted mouse model effectively prevented the degradation of heart contraction, but not ventricular hypertrophy. Electrophysiology and confocal imaging studies showed that antagomir treatment prevented the decreases in L-type Ca(2+) channel-ryanodine receptor signaling fidelity/efficiency and whole-cell Ca(2+) transients. Further studies showed that antagomir treatment stabilized junctophilin-2 expression and protected the ultrastructure of T-tubule-sarcoplasmic reticulum junctions from disruption.<br />Conclusions: MiR-24 suppression prevented the transition from compensated hypertrophy to decompensated hypertrophy, providing a potential strategy for early treatment against heart failure.
- Subjects :
- Animals
Aortic Stenosis, Subvalvular complications
Calcium Channels, L-Type physiology
Calcium Signaling physiology
Disease Progression
Drug Evaluation, Preclinical
Gene Expression Regulation
Heart Failure etiology
Heart Failure metabolism
Hypertrophy, Left Ventricular complications
Hypertrophy, Left Ventricular physiopathology
Male
Membrane Proteins antagonists & inhibitors
Mice
Mice, Inbred C57BL
MicroRNAs genetics
MicroRNAs physiology
Models, Cardiovascular
Myocardial Contraction drug effects
Myocytes, Cardiac metabolism
Myocytes, Cardiac ultrastructure
Oligonucleotides, Antisense pharmacology
Ryanodine Receptor Calcium Release Channel physiology
Sarcoplasmic Reticulum drug effects
Sarcoplasmic Reticulum physiology
Sarcoplasmic Reticulum ultrastructure
Calcium Signaling drug effects
Excitation Contraction Coupling drug effects
Heart Failure prevention & control
Hypertrophy, Left Ventricular drug therapy
MicroRNAs antagonists & inhibitors
Myocytes, Cardiac drug effects
Oligonucleotides, Antisense therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 112
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 23307820
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.112.300806