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.
Highlights
Diabetes mellitus (DM) currently affects up to 463 million people worldwide, imposing significant health and economic (USD 760 billion p.a., 12% of global health expenditure) burden (International Diabetes Federation, 2019)
We recently found that high-density lipoproteins (HDL)-bound miR-181c levels are strikingly elevated in Indigenous Australian males with diabetes-associated peripheral artery disease, a population that is disproportionately impacted by diabetic vascular complications (Morrison et al, 2021)
We have previously identified a novel anti-angiogenic role for miR-181c and in this review have highlighted how this miRNA may be dysregulated in diabetes. miR-181c expression is altered in response to hypoxia, suggesting that its regulation may be important for mediating ischaemia-driven angiogenesis in diabetes
Summary
Diabetes mellitus (DM) currently affects up to 463 million people worldwide, imposing significant health and economic (USD 760 billion p.a., 12% of global health expenditure) burden (International Diabetes Federation, 2019). When diagnosed with PAD associated with critical limb ischaemia (CLI), individuals with T2DM have an 8-fold higher amputation rate which contributes significantly to patient morbidity (Ware and Simons, 1997) This leads to an increased burden on medical care, reduced quality of life and increased risk of early death. We summarise the pathways currently known to be regulated by miR-181c which include the classical angiogenesis pathways that are dysregulated in diabetes, as well as cellular processes, such as axonal guidance and mitochondrial function We describe how these relate both directly and indirectly to angiogenesis, providing the rationale for its therapeutic potential as a novel target for the rescue of diabetes-impaired angiogenesis
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