Upregulated anti-angiogenic miR-424-5p in type 1 diabetes (model of subclinical cardiovascular disease) correlates with endothelial progenitor cells, CXCR1/2 and other parameters of vascular health
Alice Tamara, David J. Coulson, Jevi Septyani Latief, Sherin Bakhashab, Jolanta U. Weaver
Abstract
Abstract Background In spite of clinical progress, cardiovascular disease (CVD) remains the predominant cause of mortality worldwide. Overexpression studies in animals have proven miR-424-5p to have anti-angiogenic properties. As type 1 diabetes mellitus (T1DM) without CVD displays endothelial dysfunction and reduced circulating endothelial progenitor cells (cEPCs), it offers a model of subclinical CVD. Therefore, we explored miR-424-5p, cytokines and vascular health in T1DM. Methods Twenty-nine well-controlled T1DM patients with no CVD and 20-matched controls were studied. Cytokines IL8, TNF-α, IL7, VEGF-C, cEPCs/CD45 dim CD34 + CD133 + cells and ex-vivo proangiogenic cells (PACs)/fibronectin adhesion assay (FAA) were measured. MiR-424-5p in plasma and peripheral blood mononuclear cells (PBMC) along with mRNAs in PBMC was evaluated. Results We found an elevation of IL7 ( p = 0.008), IL8 ( p = 0.003), TNF-α ( p = 0.041), VEGF-C ( p = 0.013), upregulation of mRNA CXCR1 ( p = 0.009), CXCR2 ( p < 0.001) and reduction of cEPCs ( p < 0.001), PACs ( p < 0.001) and FAA ( p = 0.017) in T1DM. MiR-424-5p was upregulated in T1DM in PBMC ( p < 0.001). MiR-424-5p was negatively correlated with cEPCs ( p = 0.006), PACs ( p = 0.005) and FAA ( p < 0.001) and positively with HbA 1c ( p < 0.001), IL7 ( p = 0.008), IL8 ( p = 0.017), VEGF-C ( p = 0.007), CXCR1 ( p = 0.02) and CXCR2 ( p = 0.001). ROC curve analyses showed (1) miR-424-5p to be a biomarker for T1DM ( p < 0.001) and (2) significant upregulation of miR-424-5p, defining subclinical CVD, occurred at HbA 1c of 46.5 mmol/mol ( p = 0.002). Conclusion We validated animal research on anti-angiogenic properties of miR-424-5p in T1DM. MiR-424-5p may be a biomarker for onset of subclinical CVD at HbA 1c of 46.5 mmol/mol (pre-diabetes). Thus, miR-424-5p has potential use for CVD monitoring whilst anti-miR-424-5p-based therapies may be used to reduce CVD morbidity/mortality in T1DM.