Abstract
Oxidized low density lipoprotein (ox-LDL) has been suggested to affect endothelium-dependent vascular tone through a decreased biological activity of endothelium-derived nitric oxide (NO). Oxidative inactivation of NO is regarded as an important cause of its decreased biological activity, and in this context superoxide (O(2)) is known to inactivate NO in a chemical reaction during which peroxynitrite is formed. In this study we examined the effect of ox-LDL on the intracellular NO concentration in bovine aortic endothelial cells and whether this effect is influenced by ox-LDL binding to the endothelial receptor lectin-like ox-LDL receptor-1 (LOX-1) through the formation of reactive oxygen species and in particular of O(2). ox-LDL induced a significant dose-dependent decrease in intracellular NO concentration both in basal and stimulated conditions after less than 1 min of incubation with bovine aortic endothelial cells (p < 0.01). In the same experimental conditions ox-LDL also induced O(2) generation (p < 0.001). In the presence of radical scavengers and anti-LOX-1 monoclonal antibody, O(2) formation induced by ox-LDL was reduced (p < 0.001) with a contemporary rise in intracellular NO concentration (p < 0.001). ox-LDL did not significantly modify the ability of endothelial nitric oxide synthase to metabolize l-arginine to l-citrulline. The results of this study show that one of the pathophysiological consequences of ox-LDL binding to LOX-1 may be the inactivation of NO through an increased cellular production of O(2).
Highlights
Endothelium-dependent relaxation is impaired in animals with atherosclerosis [1,2,3], which has been linked to a decreased production and/or biological activity of endotheliumderived nitric oxide (NO)1 [4, 5]
In this study we examined the effect of Oxidized low density lipoprotein (ox-LDL) on the intracellular NO concentration in bovine aortic endothelial cells and whether this effect is influenced by ox-LDL binding to the endothelial receptor lectin-like ox-LDL receptor-1 (LOX-1) through the formation of reactive oxygen species and in particular of O2.. ox-LDL induced a significant dose-dependent decrease in intracellular NO concentration both in basal and stimulated conditions after less than 1 min of incubation with bovine aortic endothelial cells (p < 0.01)
In our experimental conditions the incubations of bovine aortic endothelial cells (BAECs) with 10 M DAF-2 DA for 10 min at 37 °C followed by stimulation with bradykinin or thrombin for 5 min generated a sharp increase of mean fluorescence intensity (MFI)
Summary
Endothelium-dependent relaxation is impaired in animals with atherosclerosis [1,2,3], which has been linked to a decreased production and/or biological activity of endotheliumderived nitric oxide (NO)1 [4, 5]. Oxidized low density lipoprotein (ox-LDL) has been observed to induce abnormalities in endothelial function, which may be relevant for the progression of atherosclerotic lesions [12]. In particular functional alterations of the endothelial cells may be involved in the reduction of vasodilation, in response to stimuli that induce NO release, in isolated arteries exposed to ox-LDL [13]. It has been suggested that ox-LDL uptake through this receptor may be involved in endothelial activation or dysfunction in atherogenesis [14]. In this context we recently reported that ox-LDL binding to LOX-1 determined a significant increase in the generation of reactive oxygen species (ROS) in endothelial cells [15]. In this report we investigated the relationship between the intracellular production of ROS and in particular of O2. and the intracellular concentration of NO in cultures of BAECs exposed to ox-LDL
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