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.

Li RC, Tao J, Guo YB, Wu HD, Liu RF, Bai Y, Lv ZZ, Luo GZ, Li LL, Wang M, Yang HQ, Gao W, Han QD, Zhang YY, Wang XJ, Xu M*, Wang SQ*. (2013) In Vivo Suppression of MicroRNA-24 Prevents the Transition Toward Decompensated Hypertrophy in Aortic-Constricted Mice. Circulation Research, 112(4):601-605.