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,Jevi Septyani Latief,David J Coulson,Jolanta U Weaver,Sherin Bakhashab

doi:10.1186/s13287-021-02332-7

Abstract

BackgroundIn 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.MethodsTwenty-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.ResultsWe 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 HbA1c (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 HbA1c of 46.5 mmol/mol (p = 0.002).ConclusionWe 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 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.

Highlights

In spite of clinical progress, cardiovascular disease (CVD) remains the predominant cause of mortality worldwide
It is associated with endothelial dysfunction and reduced indices of vascular health—circulating endothelial progenitor cells, Hills colonies, proangiogenic cells (PACs) and fibronectin adhesion assay (FAA)—known to define CVD in other patient’s groups [8, 9]
Cytokine characteristics of study participants The levels of IL7 (2.3 ± 0.6 vs 1.4 ± 0.6; p = 0.005), IL8 (4.7 ± 1.3 vs 2.8 ± 0.5; p = 0.003), TNF-α (1.6 ± 0.2 vs 1.4 ± 0.2; p = 0.041) and Vascular endothelial growth factor (VEGF)-C (63.2 ± 20.3 vs 50.8 ± 48.2; p = 0.013) were detected to be significantly greater in type 1 diabetes mellitus (T1DM) patients compared to controls as reported previously by us [11]

Summary

Introduction

In spite of clinical progress, cardiovascular disease (CVD) remains the predominant cause of mortality worldwide. We and others have demonstrated that T1DM without CVD has features of subclinical CVD [5,6,7] It is associated with endothelial dysfunction and reduced indices of vascular health—circulating endothelial progenitor cells (cEPCs), Hills colonies, proangiogenic cells (PACs) and fibronectin adhesion assay (FAA)—known to define CVD in other patient’s groups [8, 9]. This data focuses our attention on T1DM as a model of subclinical CVD

Methods

Results

Discussion

Conclusion