Advanced glycation end products, fibroblast growth factors and the development of atherosclerosis in patients with diabetes

Introduction. Atherosclerotic processes are more pronounced at diabetes mellitus (DM). Chronic hyperglycemia activated pathological mechanisms of restructuring the connective tissue, including the vascular wall. Fibroblasts are the main cellular components. Activation of the transforming growth factor (TGFß1), basic fibroblast growth factor (ß-FGF), produced by fibroblasts, inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor (α-TNF), advanced glycation endproducts (AGE) and their receptors (rAGE), may have important prognostic value.

Objective. To investigate the level AGE, TGFß1 and ß-FGF in patients with severity atherosclerosis coronary artery disease (CAD), to compare with normal blood glucose and DM.

Material and methods. The study involved two groups of patients with CAD: 56 patients of the first group had normal blood glucose and 78 patients suffered from DM type 2. The degree of coronary atherosclerosis was determined by coronary angiography (CAG) in all patients. The blood samples were collected from the aorta during CAG and cubital vein simultaneously, immediately centrifuged (15000g*min), supernatants were stored at –70*C until analysis were done. Serum was analyzed by ELISA (IFA). The critical significance level (p) for statistical hypothesis testing was set at <0.05.

Results. Average β-FGF, TGF-ß1, AGE, RAGE in the second group was significantly higher than in the first (p<0.005). Increased level of the AGE, RAGE and TGFß1 was positive correlated with low-density lipoprotein and triglycerides (R=0,049, p<0.005). IL-6 was significantly higher in the second group. There was the significant correlative relationship between the levels AGE, RAGE, TGFß1, ß-FGF and IL-6 with DM duration (R=-0,120; p=0.009), direct association with HbA_1C (R=0,429; p=0.006). There were significantly higher level of the AGE, TGFß1 and ß-FGF in aortic blood than in peripheral venous blood p<0,005). IL-6 level had opposite features: serum IL-6 was higher in venous than arterial blood. The patients with DM had three-vessel disease often (73%) then the patients without DM (R = 0,021, p<0.005), which was direct correlated with level TGFß1 (R = 0,03, p<0.005). There weren`t any differences in α-TNF level between two groups.

Discussion. High AGE, TGFß1 level and positive correlation with atherogenic lipids may indicate the role of the connective tissue remodeling in pathogenesis of the coronary atherosclerosis. As the longer DM duration led to increasing AGE, TGFß1 and IL-6 levels the chronic hyperglycemia can restructure the vascular wall. Higher AGE, TGFß1 and ß-FGF levels in aorta then in peripheral blood may show the involvement of the cardiomyocytes in these growth factors metabolism.

Conclusion. DM existence with CAD was characterized by higher AGE, RAGE, TGFß1 and IL-6 levels, which was direct correlated with the atherogenic lipids. Patients with type 2 DM and CAD had more severe coronary artery disease.