Research & Development, Nour Heart, Inc., Vienna, VA 22180, USA.
Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06032, USA.
Int J Mol Sci. 2023 Sep 30;24(19):14783. doi: 10.3390/ijms241914783.
The challenge of rapidly diagnosing myocardial ischemia in unstable angina (UA) patients presenting to the Emergency Department (ED) is due to a lack of sensitive blood biomarkers. This has prompted an investigation into microRNAs (miRNAs) related to cardiac-derived Nourin for potential diagnostic application. The Nourin protein is rapidly expressed in patients with acute coronary syndrome (ACS) (UA and acute myocardial infarction (AMI)). MicroRNAs regulate gene expression through mRNA binding and, thus, may represent potential biomarkers. We initially identified miR-137 and miR-106b and conducted a clinical validation, which demonstrated that they were highly upregulated in ACS patients, but not in healthy subjects and non-ACS controls. Using integrated comprehensive bioinformatics analysis, the present study confirms that the Nourin protein targets miR-137 and miR-106b, which are linked to myocardial ischemia and inflammation associated with ACS. Molecular docking demonstrated robust interactions between the Nourin protein and miR137/hsa-miR-106b, involving hydrogen bonds and hydrophobic interactions, with -10 kcal/mol binding energy. I-TASSER generated Nourin analogs, with the top 10 chosen for structural insights. Antigenic regions and MHCII epitopes within the Nourin SPGADGNGGEAMPGG sequence showed strong binding to HLA-DR/DQ alleles. The Cytoscape network revealed interactions of -miR137/hsa-miR--106b and Phosphatase and tensin homolog (PTEN) in myocardial ischemia. RNA Composer predicted the secondary structure of miR-106b. Schrödinger software identified key Nourin-RNA interactions critical for complex stability. The study identifies miR-137 and miR-106b as potential ACS diagnostic and therapeutic targets. This research underscores the potential of miRNAs targeting Nourin for precision ACS intervention. The analysis leverages RNA Composer, Schrödinger, and I-TASSER tools to explore interactions and structural insights. Robust Nourin-miRNA interactions are established, bolstering the case for miRNA-based interventions in ischemic injury. In conclusion, the study contributes to UA and AMI diagnosis strategies through bioinformatics-guided exploration of Nourin-targeting miRNAs. Supported by comprehensive molecular analysis, the hypoxia-induced miR-137 for cell apoptosis (a marker of cell damage) and the inflammation-induced miR-106b (a marker of inflammation) confirmed their potential clinical use as diagnostic biomarkers. This research reinforces the growing role of miR-137/hsa-miR-106b in the early diagnosis of myocardial ischemia in unstable angina patients.
不稳定型心绞痛 (UA) 患者在急诊科就诊时,迅速诊断心肌缺血的挑战源于缺乏敏感的血液生物标志物。这促使人们研究与心脏衍生的 Nourin 相关的 microRNAs (miRNAs),以期将其作为潜在的诊断应用。Nourin 蛋白在急性冠状动脉综合征 (ACS) (UA 和急性心肌梗死 (AMI)) 患者中迅速表达。miRNAs 通过与 mRNA 结合来调节基因表达,因此可能代表潜在的生物标志物。我们最初鉴定了 miR-137 和 miR-106b,并进行了临床验证,结果表明它们在 ACS 患者中高度上调,但在健康受试者和非 ACS 对照组中则没有。通过综合全面的生物信息学分析,本研究证实 Nourin 蛋白靶向 miR-137 和 miR-106b,与 ACS 相关的心肌缺血和炎症有关。分子对接表明,Nourin 蛋白与 miR137/hsa-miR-106b 之间存在强相互作用,涉及氢键和疏水相互作用,结合能为-10 kcal/mol。I-TASSER 生成了 Nourin 类似物,选择前 10 个进行结构分析。Nourin SPGADGNGGEAMPGG 序列中的抗原区域和 MHCII 表位与 HLA-DR/DQ 等位基因具有强烈的结合能力。Cytoscape 网络显示 miR-137/hsa-miR-106b 与磷酸酶和张力蛋白同源物 (PTEN) 之间的相互作用与心肌缺血有关。RNA Composer 预测了 miR-106b 的二级结构。Schrödinger 软件确定了对复合物稳定性至关重要的关键 Nourin-RNA 相互作用。该研究将 miR-137 和 miR-106b 鉴定为潜在的 ACS 诊断和治疗靶点。该研究强调了针对 Nourin 的 miRNAs 在精准 ACS 干预中的潜力。该分析利用 RNA Composer、Schrödinger 和 I-TASSER 工具来探索相互作用和结构见解。确立了强有力的 Nourin-miRNA 相互作用,为缺血性损伤的 miRNA 干预提供了支持。总之,本研究通过基于生物信息学的 Nourin 靶向 miRNA 探索,为 UA 和 AMI 的诊断策略做出了贡献。综合分子分析表明,缺氧诱导的 miR-137 用于细胞凋亡 (细胞损伤的标志物),炎症诱导的 miR-106b (炎症的标志物),证实了它们作为诊断生物标志物的潜在临床用途。该研究证实了 miR-137/hsa-miR-106b 在不稳定型心绞痛患者心肌缺血的早期诊断中的作用。