Is EV-miR-126-5p a molecular link between impaired glucose metabolism and coronary atherosclerosis?

Background Atherosclerosis is still the major cause of cardiovascular morbidity and mortality in Western Countries. Attention on cardiometabolic and vascular risk factors, including prediabetes/diabetes, hypertension, and dyslipidaemia is rising.NoncodingRNAs (ncRNAs) have emerged as key regulators of gene expression. They actively modulate molecular pathways involved in atherogenesis and circulate in the blood using extra-vesicles (EVs) as delivery carrier. Among them, miR-126-5p, known to be produced by endothelium, exerts anti-inflammatory and anti-apoptotic actions, but its association with cardiometabolic risk factors and coronary atherosclerotic disease (CAD) remains unclear. Purpose This study aimed at exploring the association of plasma EV-miR-126-5p with cardiometabolic risk factors and coronary atherosclerotic features in patients with CAD, as assessed by computerized tomography angiography (CTA). Methods A subgroup of 67 CAD patients (67.7±8.3 years; 63% males) enrolled in the HURRICANE prospective trial was studied. EVs were isolated from plasma samples by ultra-centrifugation and EV-miR-126-5p particles were quantified by digital PCR. Patients were fully characterized by cardiometabolic risk factors. CTA exams were visually and semi-quantitatively analysed according to CAD-RADS2 classification. Segment Involvement Score (SIS) and Agatston calcium score (CAC) were derived and severity and extension of disease were described using categories of CAD-RADS2 scores: Non Obstructive (CAD-RADS2 1-to-2) and Obstructive disease (CAD-RADS2 3-to-5); and Less Extensive (P1-P2) and More Extensive disease (P3-P4), respectively. Results Among cardiometabolic risk determinants, a significantly higher age and frequency of prediabetes/diabetes were present in patients with Obstructive and More Extensive disease, while significantly elevated levels of glucose and HbA1c were observed only in patients with a More Extensive disease (Fig 1). EV-miR-126-5p levels were lower in males compared to females (Fig 2A) and in prediabetes/diabetes patients compared with patients without (Fig 2B). Accordingly, EV-miR-126-5p levels were inversely correlated with glucose (p=0.006; R=−0.33) and HbA1c (p=0.043; R=−0.25), while positively correlated with adiponectin (p=0.015; R=0.297). Moreover, EV-miR-126-5p were lower in patients with Obstructive compared with patients with Non Obstructive disease (Fig 2C), and in patients with More Extensive compared with those with Less extensive disease (Fig 2D). EV-miR-126-5p levels were inversely correlated with SIS (p=0.0167; R=−0.291) and with CAC score (p=0.042; R=−0.263).Conclusions:Among cardiometabolic determinants, lower levels of EV-miR-126-5p were associated only with prediabetes/diabetes, while, among CTA-derived CAD features, with a more severe and extensive CAD. These results suggest a role for EV-miR-126-5p as a molecular link between impaired glucose metabolism and coronary atherosclerosis.