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

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/CD45dimCD34+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\u2009=\u20090.008), IL8 (p\u2009=\u20090.003), TNF-α (p\u2009=\u20090.041), VEGF-C (p\u2009=\u20090.013), upregulation of mRNA CXCR1 (p\u2009=\u20090.009), CXCR2 (p\u2009<\u20090.001) and reduction of cEPCs (p\u2009<\u20090.001), PACs (p\u2009<\u20090.001) and FAA (p\u2009=\u20090.017) in T1DM. MiR-424-5p was upregulated in T1DM in PBMC (p\u2009<\u20090.001). MiR-424-5p was negatively correlated with cEPCs (p\u2009=\u20090.006), PACs (p\u2009=\u20090.005) and FAA (p\u2009<\u20090.001) and positively with HbA1c (p\u2009<\u20090.001), IL7 (p\u2009=\u20090.008), IL8 (p\u2009=\u20090.017), VEGF-C (p\u2009=\u20090.007), CXCR1 (p\u2009=\u20090.02) and CXCR2 (p\u2009=\u20090.001). ROC curve analyses showed (1) miR-424-5p to be a biomarker for T1DM (p\u2009<\u20090.001) and (2) significant upregulation of miR-424-5p, defining subclinical CVD, occurred at HbA1c of 46.5\u2009mmol/mol (p\u2009=\u20090.002). 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 HbA1c of 46.5\u2009mmol/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.