title: Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy.
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.
authors.affiliation: From the Shanxi Medical University, Taiyuan 030001, China, Department of Pharmacology and Cell Biophysics.
authors.forename: Liwang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pharmacology and Cell Biophysics.
authors.forename: Yutian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Cell Biophysics.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Cell Biophysics.
authors.forename: Xingjiang
authors.initials: X
authors.lastname: Mu
authors.affiliation: From the Shanxi Medical University, Taiyuan 030001, China, Department of Pharmacology and Cell Biophysics.
authors.forename: Dongze
authors.initials: D
authors.lastname: Qin
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Cell Biophysics, Research Services, Veterans Affairs Hospital and Department of Medicine, and.
authors.forename: Saeed
authors.initials: S
authors.lastname: Alshahrani
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0575.
authors.forename: Michelle
authors.initials: M
authors.lastname: Nieman
authors.affiliation: Department of Pharmacology and Cell Biophysics, Department of Cardiology, Union Hospital Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China, and.
authors.forename: Jiangtong
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Pharmacology and Cell Biophysics.
authors.forename: Kobina
authors.initials: K
authors.lastname: Essandoh
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, Ontario N6A 4G5, Canada.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0575.
authors.forename: John
authors.initials: J
authors.lastname: Lorenz
authors.affiliation: Research Services, Veterans Affairs Hospital and Department of Medicine, and.
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
authors.affiliation: From the Shanxi Medical University, Taiyuan 030001, China.
authors.forename: Zhi-Qing
authors.initials: ZQ
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology and Cell Biophysics, fangg@ucmail.uc.edu.
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014161:Transduction, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C544877:MIRN223 microRNA, mouse; C000609258:MIRN223 microRNA, rat; D035683:MicroRNAs; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A
keywords: Akt PKB; cardiac hypertrophy; cardiomyocyte; microRNA (miRNA); transgenic mice