Bone Morphogenic Protein-4 Contributes to Venous Endothelial Dysfunction in Patients With Diabetes Undergoing Coronary Revascularization

Abstract

Hyperglycemia-induced venous endothelial dysfunction accelerates the progression of vein graft failure in patients with diabetes undergoing surgical coronary revascularization. Recent studies suggest the importance of bone morphogenic protein-4 (BMP4)-induced arterial endothelial dysfunction in the development of hypertension and atherosclerosis. The present study investigated the potential role of BMP4 in the pathogenesis of venous endothelial dysfunction in the setting of diabetes. Segments of saphenous vein from pigs and from patients with diabetes or patients without diabetes, as well as human umbilical venous endothelial cells (HUVECs), were used. The changes of BMP4 expression in veins from patients and in HUVECs cultured under hyperglycemic conditions were evaluated by Western blot assay. The effects of BMP4 on the production of reactive oxygen species (ROS) and endothelium-dependent venous relaxation were assessed by using dihydroethidium fluorescence and isometric tension measurements, respectively. The impaired venous endothelium-dependent relaxations (2.9%±4.8% versus control group 74.1%±10%; p<0.01) accompanied by markedly increased BMP4 expression were observed in the diabetic group. The level of BMP4 expression in HUVECs treated with high levels of glucose were elevated in a glucose concentration-dependent manner. Ex vivo treatment with the BMP4 antagonist noggin significantly improved endothelium-dependent relaxations and inhibited accumulation of ROS in saphenous veins from patients with diabetes. Noggin treatment had no effect on the venous endothelium-dependent relaxations in individuals without diabetes. Meanwhile, BMP4 inhibited acetylcholine-induced relaxation (control group, 90%±7.1% versus BMP4-treated group, 52%±12.6%; p<0.05) and enhanced ROS production in porcine saphenous veins. Such harmful effects were again reversed by noggin. The increased BMP4 expression and related ROS overproduction may play an important role in the development of hyperglycemia-induced venous endothelial dysfunction.