MicroRNA targets and biomarker validation for diabetes-associated cardiac fibrosis.

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.