Glycated high-density lipoprotein regulates reactive oxygen species and reactive nitrogen species in endothelial cells

Department of Biochemistry, Saitama Medical School, Moroyama, Saitama, Japan.
Metabolism (Impact Factor: 3.89). 02/2003; 52(1):42-9. DOI: 10.1053/meta.2003.50013
Source: PubMed


Nonenzymatic glycosylation of plasma proteins may contribute to the excess risk of developing atherosclerosis in patients with diabetes mellitus. Although it is believed that high-density lipoprotein (HDL) is glycosylated at an increased level in diabetic individuals, little is known about a possible linkage between glycated HDL and endothelial dysfunction in diabetes. To clarify whether glucose-modified HDL affects the function of endothelial cells, we first examined herein the level of H(2)O(2) generation from cultured human aortic endothelial cells (HAECs) exposed to a glycated oxidized HDL (gly-ox-HDL) prepared in vitro. Incubation for 48 hours with 100 microg/mL of gly-ox-HDL induced significant release of H(2)O(2) from cells and gly-ox-HDL-induced H(2)O(2) formation was inhibited in the presence of diphenyleneiodonium, an inhibitor of NADPH oxidase. In addition, stimulation of HAECs with gly-ox-HDL for 48 hours elicited a marked downregulation of catalase and Cu(2+), Zn(2+)-superoxide dismutase (CuZn-SOD), suggesting H(2)O(2) formation by gly-ox-HDL to be due to a disturbance involving oxidant and antioxidant enzymes in the cells. Treatment of HAECs with gly-ox-HDL attenuated the expression of endothelial nitric oxide synthase (eNOS), but not inducible nitric oxide synthase (iNOS), and this was followed by decreased production of nitric oxide (NO) by the cells. Furthermore, in vitro experiments with glycated HDL (gly-HDL) in the presence of 2 mmol/L EDTA and Cu(2+)-oxidized HDL suggested the effect of gly-HDL on endothelial function to be possibly potentiated by additional oxidative modification. Taking all of the above findings together, gly-ox-HDL may lead to the deterioration of vascular function through altered production of reactive oxygen species and reactive nitrogen species in endothelial cells.

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    • "Non-enzymic glycosylation and oxidation of HDLs is thought to occur in diabetic patients. These modified HDLs induce H2O2 production by HAECs and were shown to reduce eNOS expression associated with decreased NO production (Matsunaga et al., 2003). Human apoA-I gene transfer in a rat model of diabetes induced by streptozotocin was shown to thwart induction of aortic angiotensin AT1 receptor expression. "
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    ABSTRACT: High density lipoproteins (HDLs) represent a family of particles characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to reverse transport cholesterol from peripheral tissues back to the liver. In addition to this function, HDLs display pleiotropic effects including antioxidant, anti-apoptotic, anti-inflammatory, anti-thrombotic or anti-proteolytic properties that account for their protective action on endothelial cells (ECs). Vasodilatation via production of nitric oxide (NO) is also a hallmark of HDL action on ECs. ECs express receptors for apoA-I/HDLs that mediate intracellular signalling and potentially participate in the internalization of these particles. In this review, we will detail the different effects of HDLs on the endothelium in normal and pathological conditions with a particular focus on the potential use of HDL therapy to restore endothelial function and integrity.
    British Journal of Pharmacology 03/2013; 169(3). DOI:10.1111/bph.12174 · 4.84 Impact Factor
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    • "Decreased plasma HDL cholesterol concentration in diabetic patients is frequently associated with endothelial dysfunction, and clinical studies demonstrate that increased levels of HDL can reduce the risk of atherosclerosis progression in diabetic patients [7], [8]. Furthermore, D-HDL has impaired ability to activate eNOS, and EPC related early repair [11], [25]. However, direct demonstration that D-HDL is dysfunctional in stimulating EC proliferation and migration has not yet been reported. "
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    ABSTRACT: Background Diabetic HDL had diminished capacity to stimulate endothelial cell (EC) proliferation, migration, and adhesion to extracellular matrix. The mechanism of such dysfunction is poorly understood and we therefore sought to determine the mechanistic features of diabetic HDL dysfunction. Methodology/Principal Findings We found that the dysfunction of diabetic HDL on human umbilical vein endothelial cells (HUVECs) was associated with the down regulation of the HDL receptor protein, SR-BI. Akt-phosphorylation in HUVECs was induced in a biphasic manner by normal HDL. While diabetic HDL induced Akt phosphorylation normally after 20 minutes, the phosphorylation observed 24 hours after diabetic HDL treatment was reduced. To determine the role of SR-BI down regulation on diminished EC responses of diabetic HDL, Mouse aortic endothelial cells (MAECs) were isolated from wild type and SR-BI (−/−) mice, and treated with normal and diabetic HDL. The proliferative and migratory effects of normal HDL on wild type MAECs were greatly diminished in SR-BI (−/−) cells. In contrast, response to diabetic HDL was impaired in both types suggesting diminished effectiveness of diabetic HDL on EC proliferation and migration might be due to the down regulation of SR-BI. Additionally, SR-BI down regulation diminishes diabetic HDL’s capacity to activate Akt chronically. Conclusions/Significance Diabetic HDL was dysfunctional in promoting EC proliferation, migration, and adhesion to matrix which was associated with the down-regulation of SR-BI. Additionally, SR-BI down regulation diminishes diabetic HDL’s capacity to activate Akt chronically.
    PLoS ONE 11/2012; 7(11):e48530. DOI:10.1371/journal.pone.0048530 · 3.23 Impact Factor
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    • "Chronic exposure to reactive oxygen species (ROS) and the resulting oxidative stress are considered central components of the onset of atheroma formation [1], diabetic complications [2] [3], cell transformation and proliferation in cancer [4], and degenerative disorders and senescence [5]. Oxidative stress, viewed as the overproduction of ROS, the failure of the antioxidant defense of the organism, or both, plays a major role in human pathology [6]. "
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    ABSTRACT: Reactive oxygen species (ROS) are acknowledged generally to be multi-faceted regulators of cellular functions that trigger various pathological states when present chronically or transiently at non-physiologically high levels. Here we focus on the physiological involvement of ROS in cellular motility, with special emphasis on endothelial cells (EC). An important source of ROS within EC is the non-phagocytic NAD(P)H oxidase, and the small GTPase Rac1 plays a central role in activating this complex. Rac1 is one of the three Rho-family molecules (Rac, Rho and Cdc42) involved in the control of the actin cytoskeleton in response to various signals. In this review we examine the evidence linking ROS production, Rac1 activation and actin organization to EC motility, considering mechanisms for direct interaction of ROS and actin and the effects of ROS on proteins that regulate the actin cytoskeleton. The accumulated evidence suggests that ROS are important regulators of the actin cytoskeletal dynamics and cellular motility, and more in-depth studies are needed to understand the underlying mechanisms.
    Cardiovascular Research 08/2006; 71(2):236-46. DOI:10.1016/j.cardiores.2006.05.003 · 5.94 Impact Factor
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