In Vivo Suppression of MicroRNA-24 Prevents the Transition Toward Decompensated Hypertrophy in Aortic-Constricted Mice
    作者: 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
    刊物名称: Circulation Research
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    摘要:

    Rationale: During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca2+ 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 Ca2+ 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 Ca2+ channel–ryanodine receptor signaling fidelity/efficiency and whole-cell Ca2+ 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.

     

    Key Words:Ca2+ signaling,hypertrophic cardiomyopathy,hypertrophy,heart failure,myocardial contraction