In Vivo Suppression of MiR-24 Prevents the Transition toward Decompensated Hypertrophy in Aortic-constricted Mice
Rationale: During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca2+ channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) becomes defective, partially due to the decreased expression of a TT-SR anchoring protein, junctophilin-2 (JP2). MiR-24, a JP2 suppressing microRNA, is up-regulated in hypertrophied and failing cardiomyocytes.
Objective: To test whether miR-24 suppression can protect the structural and functional integrity of LCC-RyR signaling in hypertrophied cardiomyocytes.
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 LCC-RyR signaling fidelity/efficiency and whole-cell Ca2+ transients. Further studies showed that antagomir treatment stabilized JP2 expression and protected the ultrastructure of TT-SR junctions from disruption.
Conclusions: MiR-24 suppression prevented the transition from compensated hypertrophy to decompensated hypertrophy, providing a potential strategy for early treatment against heart failure.
- Received December 20, 2012.
- Revision received January 7, 2013.
- Accepted January 10, 2013.
- Copyright © 2013, Circulation Research