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 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. 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. 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. Conclusions: MiR-24 suppression prevented the transition from compensated hypertrophy to decompensated hypertrophy, providing a potential strategy for early treatment against heart failure.