High-Throughput Screening Identifies Micrornas that Target NOX2 and Improve Function Following Acute Myocardial Infarction
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MicroRNAs (miRNAs) are small non-coding RNAs that can regulate gene expression by inducing either degradation or translational inhibition of a target mRNA. miRNAs have been indicated to regulate up to 90% of human genes and played significant role in heart diseases. Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of reactive oxygen species (ROS) plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with Nox2 as the catalytic subunit is a major source for cardiac superoxide production. Nox2 expression is significantly increased in the infarcted area, especially in macrophages and myocytes. Mice lacking the Nox2 gene are protected from heart injury. Here we demonstrate to utilize the screening of the miRNA-targets using self-assembled cell (SAMcell) microarray to identify miRNAs that could regulate Nox2 expression and select three miRNAs, miR-106b, miR-148b, and miR-204, for further study. We use different in vitro assays to validate these miRNAs function on Nox2 expression and downstream products. After that we use acid-degradable polyketal particles that could effectively encapsulate miRNAs and deliver them into macrophages. Both in vitro and in vivo studies confirmed the PK3-miRNAs particles could inhibit Nox2 expression and activity, and significantly improve cardiac function. These results revealed new miRNAs for heart disease treatment and provided an effective strategy from miRNAs identify to in vivo delivery. Our study successfully combine the miRNAs high throughput screening system and macrophages specific delivery system and establish an easy and efficient method from screening to drug delivery. We validate this system and the selected miRNAs functions both in vitro and in vivo. This provides us new evidence and directions for not only myocardial infarction recovery, but also other inflammation related diseases.