In vivo suppression of microRNA-24 prevents the transition toward decompensated hypertrophy in aortic-constricted mice.
In vivo suppression of microRNA-24 prevents the transition toward decompensated hypertrophy in aortic-constricted mice.
复制标题
体内抑制 MicroRNA-24 可防止主动脉缩窄小鼠向失代偿性肥大转变
DOI：
10.1161/circresaha.112.300806
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发表时间：
2013-02-15
影响因子：
20.1
通讯作者：
Wang SQ
中科院分区：
文献类型：
--
作者：
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
基本原理：在从代偿性肥大到心力衰竭的转变过程中，细胞膜/T-小管中的L-型Ca 2+通道与肌浆网中的ryanodine受体之间的信号传导变得有缺陷，部分原因是T-小管-肌浆网锚定蛋白junctophilin-2的表达减少。microRNA（miR）-24是一种抑制miR的亲连接蛋白-2，在肥大和衰竭的心肌细胞中上调。目的：检测miR-24抑制是否可以保护肥大心肌细胞中L型Ca 2+通道-兰尼碱受体信号传导的结构和功能完整性。方法和结果：在心肌收缩的小鼠模型中，通过特定的阿托洛尔体内沉默miR-24有效地防止了心脏收缩的退化，但没有防止心室肥大。电生理学和共聚焦成像研究表明，西洛莫治疗防止L型钙通道-兰尼碱受体信号保真度/效率和全细胞钙瞬变的降低。进一步的研究表明，Eschomir处理稳定了junctophilin-2的表达，并保护了T-小管-肌浆网连接的超微结构免受破坏。结论：miR-24抑制阻止了从代偿性肥大向失代偿性肥大的转变，为心力衰竭的早期治疗提供了潜在的策略。
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.