Microsoft Word - 300806-R1_PAP_01_10_13

Rationale: During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca 2+ 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 Ca 2+ 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.