In vivo suppression of microRNA-24 prevents the transition toward decompensated hypertrophy in aortic-constricted mice.

Abstract

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.

• 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
• Journal: Circulation research (Circ Res) Vol. 112 Issue 4 Pg. 601-5 (Feb 15 2013) ISSN: 1524-4571 [Electronic] United States
• PMID: 23307820 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels, L-Type
• Membrane Proteins
• MicroRNAs
• Mirn24 microRNA, mouse
• Oligonucleotides, Antisense
• Ryanodine Receptor Calcium Release Channel
• junctophilin

Topics

• Animals
• Aortic Stenosis, Subvalvular (complications)
• Calcium Channels, L-Type (physiology)
• Calcium Signaling (drug effects, physiology)
• Disease Progression
• Drug Evaluation, Preclinical
• Excitation Contraction Coupling (drug effects)
• Gene Expression Regulation
• Heart Failure (etiology, metabolism, prevention & control)
• Hypertrophy, Left Ventricular (complications, drug therapy, physiopathology)
• Male
• Membrane Proteins (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• MicroRNAs (antagonists & inhibitors, genetics, physiology)
• Models, Cardiovascular
• Myocardial Contraction (drug effects)
• Myocytes, Cardiac (drug effects, metabolism, ultrastructure)
• Oligonucleotides, Antisense (pharmacology, therapeutic use)
• Ryanodine Receptor Calcium Release Channel (physiology)
• Sarcoplasmic Reticulum (drug effects, physiology, ultrastructure)