Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA 95757, USA.
Pharmacol Res. 2021 Dec;174:105941. doi: 10.1016/j.phrs.2021.105941. Epub 2021 Oct 14.
Cardiac fibrosis is one of the main characteristics of diabetic cardiomyopathy and manifests excessive accumulation of extracellular matrix proteins in the heart. Several signaling pathways have been proposed for pathogenesis of cardiac fibrosis in the diabetic heart. TGF-β/Smad2/3-dependent or independent pathway is the major signaling molecule core in the pathogenesis of cardiac fibrosis. MicroRNAs (miRNAs, miR) are ~22-nuceotide regulatory RNAs that are involved in gene silencing through the degradation of post-transcriptional mRNA or suppression of the expressed proteins. Hyperglycemia in the diabetic heart regulates expression of some miRNAs. Target molecules of miRNAs can be identified through biocomputational database initial screening and dual luciferase assay validation. miR-21, miR-150-5p, miR-155, miR-216a-3p, miR-221-3p, miR-223, and miR-451 were up-regulated in the diabetic heart and promoted cardiac fibrosis through targeting signaling pathways in cardiac fibroblasts, endothelial cells, and cardiac myocytes. miR-15a/-15b, miR-18a-5p, miR-20a-5p, miR-26b-5p, miR-29, miR-133a, miR-141, miR-146, miR-200b, miR-203, miR-222, and miR-551b-5p were down-regulated in the diabetic heart and exhibited anti-fibrosis when they were overexpressed. miRNAs are stable molecules and may reflect the pathological changes of organs. Some miRNAs have been detected in the plasma or serum in patients with diabetes mellitus or heart failure. Exploration of targets and biomarkers of miRNA may provide additional information on pathogenesis and diagnosis of cardiac fibrosis and novel targets to tackle diabetic cardiomyopathy.
心肌纤维化是糖尿病心肌病的主要特征之一，表现为心脏中外源性基质蛋白的过度积累。目前已经提出了几种信号通路来解释糖尿病心脏中心肌纤维化的发病机制。TGF-β/Smad2/3 依赖性或非依赖性通路是心肌纤维化发病机制中的主要信号分子核心。微小 RNA（miRNA，miR）是一种~22 个核苷酸的调节 RNA，通过降解转录后 mRNA 或抑制表达蛋白来参与基因沉默。糖尿病心脏中的高血糖调节某些 miRNA 的表达。通过生物计算数据库初步筛选和双荧光素酶报告基因检测验证，可以鉴定 miRNA 的靶分子。miR-21、miR-150-5p、miR-155、miR-216a-3p、miR-221-3p、miR-223 和 miR-451 在糖尿病心脏中上调，并通过靶向心脏成纤维细胞、内皮细胞和心肌细胞中的信号通路促进心肌纤维化。miR-15a/-15b、miR-18a-5p、miR-20a-5p、miR-26b-5p、miR-29、miR-133a、miR-141、miR-146、miR-200b、miR-203、miR-222 和 miR-551b-5p 在糖尿病心脏中下调，当它们过表达时表现出抗纤维化作用。miRNA 是稳定的分子，可能反映器官的病理变化。一些 miRNA 已在糖尿病或心力衰竭患者的血浆或血清中检测到。miRNA 靶标和生物标志物的探索可能为心肌纤维化的发病机制和诊断提供额外的信息，并为治疗糖尿病心肌病提供新的靶点。
