title: High-throughput screening identifies microRNAs that target Nox2 and improve function after acute myocardial infarction.
abstract: Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of ROS plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with NADPH oxidase (Nox)2 as the catalytic subunit is a major source of superoxide production, and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target. With the use of the miRNA-target screening system composed of a self-assembled cell microarray (SAMcell), three miRNAs, miR-106b, miR-148b, and miR-204, were identified that could regulate Nox2 expression and its downstream products in both human and mouse macrophages. Each of these miRNAs were encapsulated into polyketal (PK3) nanoparticles that could effectively deliver miRNAs into macrophages. Both in vitro and in vivo studies in mice confirmed that PK3-miRNAs particles could inhibit Nox2 expression and activity and significantly improve infarct size and acute cardiac function after MI. In conclusion, our results show that miR-106b, miR-148b, and miR-204 were able to improve heart function after myocardial infarction in mice by targeting Nox2 and possibly altering inflammatory cytokine production. This screening system and delivery method could have broader implications for miRNA-mediated therapeutics for cardiovascular and other diseases.NEW & NOTEWORTHYNADPH oxidase (Nox)2 is a promising target for treating cardiovascular disease, but there are no specific inhibitors. Finding endogenous signals that can target Nox2 and other inflammatory molecules is of great interest. In this study, we used high-throughput screening to identify microRNAs that target Nox2 and improve cardiac function after infarction.
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.|Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Junyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Milton E
authors.initials: ME
authors.lastname: Brown
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.
authors.forename: Hanshuo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Mario
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Srishti
authors.initials: S
authors.lastname: Bhutani
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.
authors.forename: Shenyi
authors.initials: S
authors.lastname: Yin
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: David
authors.initials: D
authors.lastname: Trac
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.|Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.|State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking University, Beijing, China; and.
authors.forename: Jianzhong Jeff
authors.initials: JJ
authors.lastname: Xi
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China; michael.davis@bme.emory.edu.|Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia.|Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Davis
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D057166:High-Throughput Screening Assays; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000235:genetics*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics*; D053758:Nanoparticles; D013481:Superoxides / Q000378:metabolism
chemical_list: C574692:MIRN204 microRNA, mouse; D008562:Membrane Glycoproteins; D035683:MicroRNAs; C554644:Mirn148 microRNA, mouse; D013481:Superoxides; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: microRNA; myocardial infarction; oxidative stress