Elevated HDL-bound miR-181c-5p level is associated with diabetic vascular complications in Australian Aboriginal people

Abstract

Aims/hypothesis Diabetes is a major burden on Australia's Indigenous population, with high rates of disease and vascular complications. Diabetic vascular complications are associated with impaired ischaemia-driven angiogenesis. MicroRNAs (miRNAs) are key players in the regulation of angiogenesis. HDL-cholesterol (HDL-c) levels are inversely associated with the risk of developing diabetic complications and HDL can carry miRNAs. HDL-miRNA profiles differ in disease states and may present as biomarkers with the capacity to act as bioactive signalling molecules. Recent studies have demonstrated that HDL becomes dysfunctional in a diabetic environment, losing its vasculo-protective effects and becoming more pro-atherogenic. We sought to determine whether HDL-associated miRNA profiles and HDL functionality were predictive of the severity of diabetic vascular complications in Australia's Indigenous population. Methods HDL was isolated from plasma samples from Indigenous participants without diabetes ('Healthy'), with type 2 diabetes mellitus ('T2DM') and with diabetes-associated macrovascular complications (specifically peripheral artery disease, 'T2DM+ Comp'). To assess HDL angiogenic capacity, human coronary artery endothelial cells were treated with PBS, reconstituted HDL (rHDL, positive control) or isolated HDL and then exposed to high-glucose (25 mmol/l) conditions. The expression levels of two anti-angiogenic miRNAs (miR-181c-5p and miR-223-3p) and one pro-angiogenic miRNA (miR-27b-3p) were measured in the HDL fraction, plasma and treated human coronary artery endothelial cells by quantitative real-time PCR. In vitro endothelial tubule formation was assessed using the Matrigel tubulogenesis assay. Results Strikingly, we found that the levels of the anti-angiogenic miRNA miR-181c-5p were 14-fold higher (1454 ± 1346%) in the HDL from Aboriginal people with diabetic complications compared with both the Healthy (100 ± 121%, p < 0.05) and T2DM (82 ± 77%, p < 0.05) groups. Interestingly, we observed a positive correlation between HDL-associated miR-181c-5p levels and disease severity (p = 0.0020). Under high-glucose conditions, cells treated with rHDL, Healthy HDL and T2DM HDL had increased numbers of tubules (rHDL: 136 ± 8%, p < 0.01; Healthy HDL: 128 ± 6%, p < 0.01; T2DM HDL: 124 ± 5%, p < 0.05) and branch points (rHDL: 138 ± 8%, p < 0.001; Healthy HDL: 128 ± 6%, p < 0.01; T2DM HDL: 127 ± 5%, p < 0.01) concomitant with elevations in mRNA levels of the key hypoxia angiogenic transcription factor HIF1A (rHDL: 140 ± 10%, p < 0.01; Healthy HDL: 136 ± 8%, p < 0.01; T2DM HDL: 133 ± 9%, p < 0.05). However, this increase in angiogenic capacity was not observed in cells treated with T2DM + Comp HDL (tubule numbers: 113 ± 6%, p = 0.32; branch points: 113 ± 5%, p = 0.28; HIF1A: 117 ± 6%, p = 0.43), which could be attributed to the increase in cellular miR-181c-5p levels (T2DM + Comp HDL: 136 ± 7% vs PBS: 100 ± 9%, p < 0.05). Conclusions/interpretation In conclusion, HDL from Aboriginal people with diabetic complications had redu...

Relationship between Peripheral Blood miR-181c, miR-101, and Cognitive Impairment in Patients with Diabetes Mellitus Complicated with Acute Stroke

“…e level of HbA1c reflects the glycemic control of patients. e toxic effect of hyperglycemia on the brain tissue of AS patients can lead to severe cerebral ischemia and hypoxia, which significantly increases the risk of CI [20]. miR-181c Emergency Medicine International 3 Emergency Medicine International and miR-101 are involved in the occurrence and development of CI by regulating mitochondrial gene histone coding and neuronal apoptosis in the hippocampus in patients with DM combined with AS [6,20].…”

“…e toxic effect of hyperglycemia on the brain tissue of AS patients can lead to severe cerebral ischemia and hypoxia, which significantly increases the risk of CI [20]. miR-181c Emergency Medicine International 3 Emergency Medicine International and miR-101 are involved in the occurrence and development of CI by regulating mitochondrial gene histone coding and neuronal apoptosis in the hippocampus in patients with DM combined with AS [6,20]. In this study, ROC curve was used to evaluate the diagnostic value of peripheral blood miR-181c and miR-101 expression for CI in patients with DM complicated with AS.…”

lncRNA SNHG1 induced by SP1 regulates bone remodeling and angiogenesis via sponging miR-181c-5p and modulating SFRP1/Wnt signaling pathway

“…These findings were also uncovered by Murodumi et al work (Murodumi et al 2020 ). Notably, miR-181c-5p was considered as a anti-angiogenic miRNA which was correlated to impaired angiogenic capacity in diabetes (Morrison et al 2021 ). Similar data was found in our research.…”

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

“…Low HDL levels are an independent risk factor for the development of T2DM (von Eckardstein et al, 2000) and are associated with an increased risk of diabetes-associated microvascular complications (Morton et al, 2018). We recently found that 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). HDL becomes dysfunctional in a diabetic environment, losing its vasculoprotective properties and becoming pro-atherogenic (Femlak et al, 2017).…”

“…HDL becomes dysfunctional in a diabetic environment, losing its vasculoprotective properties and becoming pro-atherogenic (Femlak et al, 2017). Treatment of HCAECs with extracted HDL from these individuals resulted in impaired tubule formation and an inability to induce HIF-1α expression (Morrison et al, 2021). This suggests that higher naturally occurring amounts of HDLbound miR-181c may result in dysfunctional HDL and contribute to the loss of its pro-angiogenic effects in diabetes.…”