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J Biol Chem. 2016 Jul 22;291(30):15700-13. doi: 10.1074/jbc.M116.715805. Epub 2016 May 20.

Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy.

Author information

1
From the Shanxi Medical University, Taiyuan 030001, China, Department of Pharmacology and Cell Biophysics.
2
Department of Pharmacology and Cell Biophysics.
3
Department of Pathology and Laboratory Medicine.
4
Department of Pharmacology and Cell Biophysics, Research Services, Veterans Affairs Hospital and Department of Medicine, and.
5
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0575.
6
Department of Pharmacology and Cell Biophysics, Department of Cardiology, Union Hospital Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China, and.
7
Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada.
8
Research Services, Veterans Affairs Hospital and Department of Medicine, and.
9
From the Shanxi Medical University, Taiyuan 030001, China.
10
Department of Pharmacology and Cell Biophysics, fangg@ucmail.uc.edu.

Abstract

MicroRNAs (miRNAs) have been extensively examined in pathological cardiac hypertrophy. However, few studies focused on profiling the miRNA alterations in physiological hypertrophic hearts. In this study we generated a transgenic mouse model with cardiac-specific overexpression of miR-223. Our results showed that elevation of miR-223 caused physiological cardiac hypertrophy with enhanced cardiac function but no fibrosis. Using the next generation RNA sequencing, we observed that most of dys-regulated genes (e.g. Atf3/5, Egr1/3, Sfrp2, Itgb1, Ndrg4, Akip1, Postn, Rxfp1, and Egln3) in miR-223-transgenic hearts were associated with cell growth, but they were not directly targeted by miR-223. Interestingly, these dys-regulated genes are known to regulate the Akt signaling pathway. We further identified that miR-223 directly interacted with 3'-UTRs of FBXW7 and Acvr2a, two negative regulators of the Akt signaling. However, we also validated that miR-223 directly inhibited the expression of IGF-1R and β1-integrin, two positive regulators of the Akt signaling. Lastly, Western blotting did reveal that Akt was activated in miR-223-overexpressing hearts. Adenovirus-mediated overexpression of miR-223 in neonatal rat cardiomyocytes induced cell hypertrophy, which was blocked by the addition of MK2206, a specific inhibitor of Akt Taken together, these data represent the first piece of work showing that miR-223 tips the balance of promotion and inactivation of Akt signaling cascades toward activation of Akt, a key regulator of physiological cardiac hypertrophy. Thus, our study suggests that the ultimate phenotype outcome of a miRNA may be decided by the secondary net effects of the whole target network rather than by several primary direct targets in an organ/tissue.

KEYWORDS:

Akt PKB; cardiac hypertrophy; cardiomyocyte; microRNA (miRNA); transgenic mice

PMID:
27226563
PMCID:
PMC4957053
DOI:
10.1074/jbc.M116.715805
[Indexed for MEDLINE]
Free PMC Article

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