Emerging Roles for MicroRNAs in Diabetic Microvascular Disease: Novel Targets for Therapy

Abstract

Chronic, low-grade systemic inflammation and impaired microvascular function are critical hallmarks in the development of insulin resistance. Accordingly, insulin resistance is a major risk factor for type 2 diabetes and cardiovascular disease. Accumulating studies demonstrate that restoration of impaired function of the diabetic macro- and microvasculature may ameliorate a range of cardiovascular disease states and diabetes-associated complications. In this review, we focus on the emerging role of microRNAs (miRNAs), noncoding RNAs that fine-tune target gene expression and signaling pathways, in insulin-responsive tissues and cell types important for maintaining optimal vascular homeostasis and preventing the sequelae of diabetes-induced end organ injury. We highlight current pathophysiological paradigms of miRNAs and their targets involved in regulating the diabetic microvasculature in a range of diabetes-associated complications such as retinopathy, nephropathy, wound healing, and myocardial injury. We provide an update of the potential use of circulating miRNAs diagnostically in type I or type II diabetes. Finally, we discuss emerging delivery platforms for manipulating miRNA expression or function as the next frontier in therapeutic intervention to improve diabetes-associated microvascular dysfunction and its attendant clinical consequences.

Figure 1.

The biogenesis of miRNA begins with the transcription of miRNA to pri-miRNA in the nucleus. The pri-miRNA is cleaved by the Drosha/DGCR8 complex to form premiRNA, which can then be exported from the nucleus to the cytoplasm by exportin5. In the cytoplasm, premiRNA is further processed into the mature miRNA duplex by Dicer. One strand (usually the guide strand) of the mature miRNA forms a complex with Dicer and the Argonaute protein, known as the miRNA-containing RISC, where miRNA binds to the 3′ UTR of its target mRNA, resulting in the degradation (if the miRNA:mRNA duplex complementarity is perfect) or suppression of the translation of the target mRNA (if the complementarity is not perfect).

Figure 2.

miR-181b improves endothelial dysfunction and consequently improves glucose homeostasis and insulin sensitivity in white adipose tissue by targeting the phosphatase PHLPP2 and reducing its expression. Reduced PHLPP2 enhances insulin signaling and AKT and eNOS expression.

Figure 3.

miRNA regulation of insulin signaling and glucose homeostasis. Many miRNAs have been identified to regulate insulin signaling in adipose tissue, liver, and skeletal muscle. miR-181b targets the phosphatase PHLPP2 in ECs of adipose tissue. miR-122, miR-103, miR-802, miR-143, and miR-26a regulate insulin signaling in the liver by regulating the expression of PTP1B, Cav-1, Hnf1b, ORP8, ACSL3, and PKCδ. miR-503, miR-125b, and miR-135a act in skeletal muscle on targets, including EFNB2 and VEGFA, IGF2, and IRS2, respectively. Endothelial-enriched miRNAs are highlighted in red.

Figure 4.

miRNA regulation of diabetic wound healing and myocardial angiogenesis. These miRNAs are involved in regulating diabetic wound healing and myocardial angiogenesis through effects on their targets that control cell proliferation, migration, apoptosis, and endothelial microvascular function. In response to diabetic conditions, several miRNAs are dysregulated (marked with an arrow).