The Role of miR-181c in Mechanisms of Diabetes-Impaired Angiogenesis: An Emerging Therapeutic Target for Diabetic Vascular Complications

Abstract

Diabetes mellitus is estimated to affect up to 700 million people by the year 2045, contributing to an immense health and economic burden. People living with diabetes have a higher risk of developing numerous debilitating vascular complications, leading to an increased need for medical care, a reduced quality of life and increased risk of early death. Current treatments are not satisfactory for many patients who suffer from impaired angiogenesis in response to ischaemia, increasing their risk of ischaemic cardiovascular conditions. These vascular pathologies are characterised by endothelial dysfunction and abnormal angiogenesis, amongst a host of impaired signaling pathways. Therapeutic stimulation of angiogenesis holds promise for the treatment of diabetic vascular complications that stem from impaired ischaemic responses. However, despite significant effort and research, there are no established therapies that directly stimulate angiogenesis to improve ischaemic complications such as ischaemic heart disease and peripheral artery disease, highlighting the immense unmet need. However, despite significant effort and research, there are no established therapies that directly stimulate angiogenesis in a clinical setting, highlighting the immense unmet need. MicroRNAs (miRNAs) are emerging as powerful targets for multifaceted diseases including diabetes and cardiovascular disease. This review highlights the potential role of microRNAs as therapeutic targets for rescuing diabetes-impaired angiogenesis, with a specific focus on miR-181c, which we have previously identified as an important angiogenic regulator. Here we summarise the pathways currently known to be regulated by miR-181c, which include the classical angiogenesis pathways that are dysregulated in diabetes, mitochondrial function and axonal guidance, and describe how these relate both directly and indirectly to angiogenesis. The pleiotropic actions of miR-181c across multiple key angiogenic signaling pathways and critical cellular processes highlight its therapeutic potential as a novel target for treating diabetic vascular complications.

Micro-RNA 92a as a Therapeutic Target for Cardiac Microvascular Dysfunction in Diabetes

“…In this context, several micro-RNAs have been shown to be dysregulated in diabetes [ 17 ]. In fact, hyperglycemia can per se dysregulate subcellular components of micro-RNA biogenesis and processing [ 18 ]. Herein, miR-92a has been shown to be among micro-RNAs upregulated in the hearts of diabetic pig models of type I DM.…”

Mitochondrion-targeted RNA therapies as a potential treatment strategy for mitochondrial diseases

“…mitomiRNAs) have been found to regulate mitochondrial translation and even transcription. 108 , 109 , 110 , 111 ASO and siRNA therapeutic agents have been shown to suppress translation of their target mitochondrial mRNAs. 98 , 112 However, whether the siRNA-induced mitochondrial gene silencing follows an RNAi-like, antisense-based, or different mechanism is unknown.…”

“… 165 miRNA (various miRNAs; e.g., miR-1, miR-181c, miR-378, and others); pre-miRNAs). 108 , 110 , 111 , 145 , 167 , 168 , 169 Cytosolic function: repress gene expression at the post-transcriptional level. Mitochondrial function: stimulate or inhibit mitochondrial gene expression, suppress mtDNA transcription, cytosol-mitochondrion crosstalk.…”

Dynamically Bioresponsive DNA Hydrogel Incorporated with Dual-Functional Stem Cells from Apical Papilla-Derived Exosomes Promotes Diabetic Bone Regeneration

“…This pathological status continuously accumulates neutrophils, dendritic cells, and macrophages at the defect site to stimulate excess expression of proinflammatory markers, such as matrix metalloproteinases (MMPs). − This further leads to continuous recruitment of immune cells, suppression of growth factors, and tissue degradation. , Thus, an undesirable accumulation of MMPs can be associated with hindrance to the healing process; therefore, this pathological cue in turn can reflect the dynamic inflammatory severity under the DM conditions. Consequent to the abnormal cellular and molecular interactions, persistent inflammation suppresses proliferation, differentiation, and bone-forming capacity of osteoblastic cells, which further impairs bone regeneration. , In the meantime, dysfunction of endothelial cells during DM results in microvascular complications, thereby limiting the process of bone regeneration in consideration of the richness of the vascular network in bone. , Currently, the acceptable treatment for patients suffering from incomplete bone healing is bone grafting, using either autografts or allografts. However, these approaches are restricted by limited supply, insufficient vascularization, and issues arising especially due to the negligence of the microenvironment at pathological sites in patients with metabolic disorders. , Thus, efficient approaches to regenerate bone under diabetic conditions are urgently needed.…”

“…9,10 In the meantime, dysfunction of endothelial cells during DM results in microvascular complications, thereby limiting the process of bone regeneration in consideration of the richness of the vascular network in bone. 11,12 Currently, the acceptable treatment for patients suffering from incomplete bone healing is bone grafting, using either autografts or allografts. However, these approaches are restricted by limited supply, insufficient vascularization, and issues arising especially due to the negligence of the microenvironment at pathological sites in patients with metabolic disorders.…”