Induction of apoptosis by high proinsulin and glucose in cultured human umbilical vein endothelial cells is mediated by reactive oxygen species

Abstract

Several lines of evidence suggest that endothelial dysfunction and damage present early steps in the pathophysiology of vascular complications in diabetes mellitus [1±3]. Several studies using cultured endothelial cells clearly show that incubation of these cells with high concentrations of glucose leads to severe changes in the proliferation, the adhesive and synthetic properties [1]. Consequently, regulation of vascular relaxation by endothelium becomes disturbed in diabetes [2,3]. In addition to glucose, high concentrations of proinsulin have been shown to promote the synthesis of the plasminogen activator inhibitor type-1 (PAI-1) [4]. This observation indicates that endothelial function can be directly influenced not only by glucose, but also by proinsulin. Thus, high proinsulin levels may contribute to the development of vascular complications in diabetes, if secreted excessively. In line with this assumption proinsulin is increased in the late pre-insulin-dependent diabetes mellitus [5] and especially in non-insulin-dependent diabetic patients with abnormal prohormone convertase PC2 and PC3 activity [6] or with a point mutation in the Diabetologia (1998)

C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells

“…In high-glucose-exposed endothelial cells, cellular apoptosis involves oxidative-stress-triggered activation of the NF-κB pathway [7,10] which, in turn, suppresses BCL-2 levels and activates caspase-3 activity [10,44]. We have previously observed that C-peptide interferes with glucose-induced nuclear translocation of the NF-κB p65/p50 subunits in HAEC, and reduces endothelial dysfunction [29].…”

“…It has been reported that high glucose increases ROS generation in HAEC [2][3][4] and triggers apoptosis [6,7,10]. ROS production causes apoptotic cell death in endothelial cells [5,7,10] and plays an important role in the development of diabetic vascular complications [2,4].…”

“…ROS production causes apoptotic cell death in endothelial cells [5,7,10] and plays an important role in the development of diabetic vascular complications [2,4]. Indeed, it has been shown that antioxidant agents rescue hyperglycaemia-induced endothelial dysfunction and reduce the risk of coronary heart disease [35,36].…”

“…High glucose damages endothelial cells by increasing oxidative stress through generation of reactive oxygen species (ROS) [2][3][4], activation of the death protease caspase-3 [5], and inducing apoptosis [6,7]. ROS are powerful cellular activators of the nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) pathway [8,9], which regulates activation of a series of cytokine and adhesion molecule genes that results in the adhesion of leucocytes to endothelial cells and release of cytotoxic molecules.…”

Caspase-3 Activation Triggers Extracellular Cathepsin L Release and Endorepellin Proteolysis

“…4 is increasingly recognized as an important component of the "response to injury" process, as most clinical risk factors of atherosclerosis (such as hypertension (1,2), hyperglycemia (3,4), oxidized low density lipoproteins (LDLs) (5,6) and oxidative stress (7)) induce EC apoptosis. Interventions aimed at preventing EC apoptosis in animal models of transplant vasculopathy, an immune-mediated form of atherosclerosis, prevent neointima formation, indicating that EC apoptosis is an important pro-atherosclerotic trigger (8 -13).…”