Yang Junyu, Brown Milton E, Zhang Hanshuo, Martinez Mario, Zhao Zhihua, Bhutani Srishti, Yin Shenyi, Trac David, Xi Jianzhong Jeff, Davis Michael E
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.
Am J Physiol Heart Circ Physiol. 2017 May 1;312(5):H1002-H1012. doi: 10.1152/ajpheart.00685.2016. Epub 2017 Feb 24.
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. NADPH 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.
心肌梗死（MI）是心力衰竭最常见的病因。活性氧（ROS）的过度产生在心肌梗死后心脏重塑的发病机制中起关键作用。以NADPH氧化酶（Nox）2作为催化亚基的NADPH是超氧化物产生的主要来源，其表达在梗死心肌中显著增加，尤其是浸润的巨噬细胞。虽然微小RNA（miRNA）是基因表达的有效调节因子，在心脏病中起重要作用，但仍缺乏有效的方法来鉴定靶向治疗心肌梗死重要病理基因的miRNA。因此，总体目标是建立一种以Nox2为关键靶点的miRNA筛选和递送系统，以改善心肌梗死后的心功能。通过使用由自组装细胞微阵列（SAMcell）组成的miRNA靶点筛选系统，鉴定出三种miRNA，即miR-106b、miR-148b和miR-204，它们可以调节人和小鼠巨噬细胞中Nox2的表达及其下游产物。这些miRNA中的每一种都被封装到聚缩醛（PK3）纳米颗粒中，该纳米颗粒可以有效地将miRNA递送至巨噬细胞中。小鼠的体外和体内研究均证实，PK3-miRNA颗粒可以抑制Nox2的表达和活性，并显著改善心肌梗死后的梗死面积和急性心功能。总之，我们的结果表明，miR-106b、miR-148b和miR-204能够通过靶向Nox2并可能改变炎性细胞因子的产生来改善小鼠心肌梗死后的心功能。这种筛选系统和递送方法可能对miRNA介导的心血管疾病和其他疾病的治疗具有更广泛的意义。NADPH氧化酶（Nox）2是治疗心血管疾病的一个有前景的靶点，但目前尚无特异性抑制剂。寻找能够靶向Nox2和其他炎性分子的内源性信号备受关注。在本研究中，我们使用高通量筛选来鉴定靶向Nox2并改善梗死后心功能的微小RNA。
