IDF21-0426 Carbamylated LDL and soluble LOX-1 – potential serum biomarkers for coronary artery disease in type 2 diabetes mellitus

Abstract

Background: Carbamylated low-density lipoprotein (cLDL) is the most abundant modified LDL isoform in human blood, but it has been investigated only in the context of chronic kidney disease since uremia provides a favourable chemical environment for this posttranslational modification. However, it has been discovered that the proinflammatory enzyme myeloperoxidase catalyses an alternative urea-independent mechanism of carbamylation. Most of the proatherogenic properties of cLDL are mediated by the scavenger lectin-like oxidized LDL receptor-1 (LOX-1). LOX-1 has been delineated as a critical player in vascular inflammation and in atherosclerotic plaque formation, destabilization, erosion and rupture. The cLDL-LOX-1 interaction triggers prooxidative and proinflammatory responses. Moreover, LOX-1 has also been identified as a receptor for C-reactive protein (CRP), a classic acute-phase reactant widely used in the clinical practice as a cardiovascular risk biomarker. The soluble form of LOX-1 (sLOX-1) reflects the expression of the membrane receptor and it has recently been suggested as a biomarker of vascular diseases. It is well-established that type 2 diabetes mellitus (T2DM) is a prominent risk factor for coronary artery disease (CAD) and inflammation is involved in the pathogenesis of both T2DM and atherosclerosis. However, the possible role and relationships between cLDL, sLOX-1 and CRP in T2DM with and without CAD have not been investigated yet. Aim: To explore the possible role of cLDL and sLOX-1 as potential biomarkers for CAD in T2DM patients and to evaluate the correlations between serum cLDL, sLOX-1 and high-sensitivity-CRP (hs-CRP). Method: The serum levels of cLDL, sLOX-1 and hs-CRP were measured by ELISA in 44 heathy controls, 67 patients with uncomplicated T2DM and 36 diabetic subjects complicated by CAD but without renal impairments. Results: Patients with uncomplicated T2DM had significantly higher serum levels of both cLDL and hs-CRP than the healthy controls, but lower in comparison to T2DM + CAD subjects. In contrast, there was no significant difference in sLOX-1 concentrations between T2DM patient and the healthy volunteers, but T2DM + CAD cohort had higher serum levels of sLOX-1 compared both to the control and uncomplicated T2DM groups. The receiver-operating characteristic analysis showed that cLDL and sLOX-1 had a significant potential to identify CAD among the diabetic patients with diagnostic sensitivity and specificity similar to those of hs-CRP. Elevated serum levels of cLDL and sLOX-1 were associated with a higher risk of CAD development among T2DM subjects (OR 4.07; 95% CI: 1.71 – 9.69, p = 0.001 and OR 2.82; 95% CI: 1.22 – 6.57, p = 0.014, respectively). Furthermore, the level of cLDL correlated positively and significantly with hs-CRP(r = 0.345, p = 0.039) and tended to correlate positively with sLOX-1 (r = 0.317, p = 0.059) only in T2DM + CAD subjects. Discussion: In conclusion, a positive feedback might exist between cLDL, CRP and LOX-1 and the interplay between them might be involved in the development of CAD in diabetic patients. The present study also elucidates the potential of cLDL and sLOX-1 as biomarkers for the diagnosis and risk assessment of CAD among T2DM population.