In Vivo Suppression of MicroRNA-24 Prevents the Transition Toward Decompensated Hypertrophy in Aortic-Constricted Mice

• DOI: 10.1161/circresaha.112.300806
• Publication Date: 2013-01-11T01:52:42Z
• Authors: Rong-Chang Li; Jin Tao; Yun-Bo Guo; Hao-Di Wu; Rui-Feng Liu; Yan Bai; Zhi-Zhen Lv; Guan-Zheng Luo; Lin-Lin Li; Meng Wang; Hua-Qian Yang; Wei Gao; Qi-De Han; You-Yi Zhang; Xiu-Jie Wang; Ming Xu; Shi-Qiang Wang
• Keywords: Heart Failure; Male; 0301 basic medicine; Calcium Channels, L-Type; Drug Evaluation, Preclinical; Models, Cardiovascular; Membrane Proteins; Ryanodine Receptor Calcium Release Channel; Oligonucleotides, Antisense; Aortic Stenosis, Subvalvular; Myocardial Contraction; Mice, Inbred C57BL; Mice; MicroRNAs; 03 medical and health sciences; Gene Expression Regulation; Disease Progression; Animals; Hypertrophy, Left Ventricular; Myocytes, Cardiac; Calcium Signaling; Excitation Contraction Coupling

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.