Vascular endothelium as a target of beraprost sodium and fenofibrate for antiatherosclerotic therapy in type 2 diabetes mellitus

Abstract

Diabetes mellitus is an important risk factor for cardiovascular morbidity and mortality. The metabolic abnormalities caused by diabetes mellitus induce vascular endothelial dysfunction that predisposes patients with diabetes mellitus to atherosclerosis. Two mega clinical trials showed that intensive glycemic control does not have favorable effects on reducing macrovascular events although it demonstrated significant reductions in microvascular complications. It is becoming worthwhile to clarify the beneficial effects of tight controls on blood pressure, serum lipids, and postprandial hyperglycemia to prevent atherosclerosis in patients with type 2 diabetes mellitus. Here, we focus on vascular endothelium as a target of the prostaglandin I2 analog beraprost sodium and the peroxisome proliferators-activated receptor alpha activator fenofibrate for the prevention and treatment of atherosclerosis in patients with type 2 diabetes mellitus. Beraprost sodium lowered circulating vascular cell adhesion molecule- 1 (VCAM-1) concentration and prevented the progression of carotid atherosclerosis in type 2 diabetic patients, probably through inhibiting VCAM-1 expression in vascular endothelium. Fenofibrate up-regulated endothelial nitric oxide synthase expression, which may explain its effects to improve endothelium-dependent vasodilatation and to prevent the progression of coronary atherosclerosis. The approaches to target the molecules expressed in vascular endothelium will become important for preventing the atherosclerosis in type 2 diabetes mellitus.

Figure 1

Relationship between serum circulating vascular cell adhesion molecule (VCAM)-1 and mean intima-medial thickness (mIMT) of carotid arteries in 101 patients with type 2 diabetic mellitus.

Figure 2

(a) Effect of beraprost on cell surface VCAM-1 level in vascular endothelial cells. Vascular endothelial cells were treated for 15 minutes with or without the indicated concentrations of beraprost, and then the cells were stimulated with (hatched bars) or without (open bars) 0.1 ng/mL TNF-α for 2 hours. Cell surface VCAM-1 was determined by whole cell ELISA. Data are means ± SE. *p < 0.001 vs TNF-α only, by ANOVA. (b) Effects of beraprost on U937 cell adhesion to TNF-α-stimulated vascular endothelial cells. Vascular endothelial cells were treated for 15 minutes with or without 10⁻⁵ mol/L beraprost and then stimulated with or without 0.1 ng/mL TNF-α for 2 hours. Data are means ± SE. Abbreviations: ANOVA, analysis of variance; ELISA, enzyme-linked immunoabsorbent assay; OD, optical density; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule.

Figure 3

Changes in circulating vascular cell adhesion molecule (VCAM-1) level (a) and mean intima-medial thickness (mIMT) of common carotid arteries (b) in 25 patients with type 2 diabetes mellitus receiving (n = 11) or not receiving (n = 14) beraprost for 3 years. Data are means ± SE.

Figure 4

Changes in mean intima-medial thickness (mIMT) of common carotid arteries in 10 patients with type 2 diabetes mellitus treated with beraprost for 8 years. Data are means ± SE. p = 0.44, by ANOVA (analysis of variance).

Figure 5

Effects of fenofibrate on endothelial nitric oxide synthase (eNOS) activity and its protein levels in vascular endothelial cells. Vascular endothelial cells were treated for 48 hours with the indicated concentrations of fenofibrate. Data are means ± SE. *p < 0.005, **p < 0.0001 vs control, by ANOVA (analysis of variance).