Impact of glycated LDL on endothelial nitric oxide synthase in vascular endothelial cells: involvement of transmembrane signaling and endoplasmic reticulum stress (original) (raw)
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Hyperglycemia reduces nitric oxide synthase and glycogen synthase activity in endothelial cells
Nitric Oxide, 2002
Hyperglycemia is considered a primary cause of diabetic vascular complications. A hallmark of vascular disease is endothelial cell dysfunction characterized by diminished nitric-oxide (NO)-dependent phenomena such as vasodilation, angiogenesis, and vascular maintenance. This study was designed to investigate the effects of a high level of D D-glucose on endothelial NO response, oxidative stress, and glucose metabolism. Bovine aortic endothelial cells (BAECs) were pretreated with a high concentration of glucose (HG) (22 mmol/L) for at least 2 weeks and compared with control cells exposed to 5 mmol/L glucose (NG). The effect of chronic hyperglycemia on endothelial NO-synthase (eNOS) activity and expression, glycogen synthase (GS) activity, extracellular-signalregulated kinase (ERK 1,2), p38, Akt expression, and Cu/Zn superoxide-dismutse (SOD-1) activity and expression were determined. Western blot analysis showed that eNOS protein expression decreased in HG cells and was accompanied by diminished eNOS activity. The activity of GS was also significantly lower in the HG cells than in NG cells, 25:0 AE 17:4 and 89 AE 22:5 nmol UDP-glucose Á mg protein À1 Â min À1 , respectively. Western blot analysis revealed a 40-60% decrease in ERK 1,2 and p38 protein levels, small modification of phosphorylated Akt expression, and a 30% increase in SOD-1 protein expression in HG cells. Although SOD expression was increased, no change was observed in SOD activity. These results support the findings that vascular dysfunction due to exposure to pathologically high D D-glucose concentrations may be caused by impairment of the NO pathway and increased oxidative stress accompanied by altered glucose metabolism.
Impairment of vascular endothelial nitric oxide synthase activity by advanced glycation end products
The FASEB Journal, 2003
Endothelial damage is believed to play a key role in the development of both micro-and macrovascular disease in diabetes, and advanced glycation end products (AGEs) may contribute importantly to this. To determine whether glucose-derived AGEs can cause endothelial dysfunction, we examined the effects of albumin AGE-modified by glucose (AGE-Glu) both in vivo, after injection into rabbit femoral artery, and in vitro on rabbit aortic rings and cultured human umbilical vein endothelial cells (HUVEC). Exposure of blood vessels to AGE-Glu, in vivo and in vitro, inhibited endothelium-dependent vasorelaxation, whereas unmodified albumin did not. In isolated rabbit aorta, this effect was reversible after AGE-Glu washout, and the response to the endothelium-independent vasodilator sodium nitroprusside was unaffected by AGE-Glu. In HUVEC, AGE-Glu inhibited endothelial nitric oxide synthase activity, and this was associated with a decrease in serine phosphorylation of this enzyme. Longer term (72 h) incubation decreased HUVEC viability. Use of specific antibodies demonstrated that these effects were mediated by N ε-(carboxymethyl)lysine (CML), an important AGE found in vivo, and by the AGE-R1 receptor. Furthermore, these effects all occurred at CML concentrations similar to those found in the plasma of diabetic patients. These results suggest an important role of AGE in the pathogenesis of diabetic vasculopathy. Key words: diabetes mellitus • vasodilation • endothelial function • AGE proteins V ascular disease, both microvascular and atherosclerotic, is the foremost complication of diabetes mellitus, accounting for much excess morbidity and mortality (1). Vascular endothelial injury is an early event in the pathogenesis of atherosclerosis (2), and microalbuminuria (the earliest evidence of glomerular endothelial injury) is a strong risk factor for myocardial infarction in diabetic patients (3). Endothelial nitric oxide (NO) biosynthesis protects against atherosclerosis (4), and there is evidence that endothelial function is abnormal in diabetes, both in animal models (5-7) and in diabetic patients (8-10). However, the mechanism whereby diabetes mellitus leads to endothelial dysfunction is incompletely understood. The accumulation of advanced glycation end products (AGEs) is one of several hypotheses proposed to explain the link between hyperglycemia and the development of vascular complications of diabetes (11, 12). AGEs are characterized by fluorescence, brown color, and
Journal of Biological Chemistry, 2003
Recent studies have indicated that insulin activates endothelial nitric-oxide synthase (eNOS) by protein kinase B (PKB)-mediated phosphorylation at Ser 1177 in endothelial cells. Because hyperglycemia contributes to endothelial dysfunction and decreased NO availability in types 1 and 2 diabetes mellitus, we have studied the effects of high glucose (25 mM, 48 h) on insulin signaling pathways that regulate NO production in human aortic endothelial cells. High glucose inhibited insulin-stimulated NO synthesis but was without effect on NO synthesis stimulated by increasing intracellular Ca 2؉ concentration. This was accompanied by reduced expression of IRS-2 and attenuated insulin-stimulated recruitment of PI3K to IRS-1 and IRS-2, yet insulin-stimulated PKB activity and phosphorylation of eNOS at Ser 1177 were unaffected. Inhibition of insulin-stimulated NO synthesis by high glucose was unaffected by an inhibitor of PKC. Furthermore, high glucose down-regulated the expression of CAP and Cbl, and insulin-stimulated Cbl phosphorylation, components of an insulin signaling cascade previously characterized in adipocytes. These data suggest that high glucose specifically inhibits insulin-stimulated NO synthesis and down-regulates some aspects of insulin signaling, including the CAP-Cbl signaling pathway, yet this is not a result of reduced PKBmediated eNOS phosphorylation at Ser 1177 . Therefore, we propose that phosphorylation of eNOS at Ser 1177 is not sufficient to stimulate NO production in cells cultured at 25 mM glucose.
Current Vascular Pharmacology, 2010
The vascular manifestations associated with diabetes mellitus (DM) result from the dysfunction of several vascular physiology components mainly involving the endothelium, vascular smooth muscle and platelets. It is also known that hyperglycemia-induced oxidative stress plays a role in the development of this dysfunction. This review considers the basic physiology of the endothelium, especially related to the synthesis and function of nitric oxide. We also discuss the pathophysiology of vascular disease associated with DM. This includes the role of hyperglycemia in the induction of oxidative stress and the role of advanced glycation end-products. We also consider therapeutic strategies.
The formation of advanced glycation end-products (AGEs), also called the Maillard reaction, occurs ubiquitously and irreversibly in patients with diabetes mellitus and its consequences is especially relevant to many inflammatory events leading to vascular dysfunctions and organ injury. The present review intend to highlight some aspects relevant to nitric oxide synthases, advanced glycation end-products and their receptors as well as the mechanisms by which AGEs is able to modulate the synthesis of nitric oxide (NO), either by NO quenching, modification of enzyme structure or up- and down-regulation of gene expression. Finally, other RAGE ligands different from AGE, but relevant in the context of inflammation, are presented as new modulators of nitric oxide synthesis.
https://www.ijrrjournal.com/IJRR\_Vol.9\_Issue.1\_Jan2022/IJRR-Abstract041.html, 2022
Diabetes mellitus type 2 (T2DM) has been a global health problem. Current studies have shown that the increased mortality and morbidity in T2DM are related to vascular complications. The vascular complications were caused by increased reactive oxygen species (ROS) associated with chronic hyperglycemia and insulin resistance. The increase of ROS in T2DM was influenced by the p38 MAPK pathway which is directly related to the modulation of nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) of endothelium cells. The decrease of NO by eNOS also has a connection with an event known as eNOS uncoupling. The decrease of eNOS plays a role in the pathogenesis of T2DM and its vascular complications such as increased inflammatory pro-cytokine, activation of NADPH pathway, increased of AGEs, VCAM-1, ICAM-1, and also the activation of protein kinase c and Rho-kinase pathway. Some interventions indirectly or directly have modulated NO relayed to its work targets such as oral antidiabetic drugs (metformin, sulfonylurea, and acarbose) or some polyphenol compounds such as emodin, α-Lipoic acid, curcumin, and olive oil. Modulation of NO in these interventions can be strong evidence that NO can be a target for further therapy in the management of T2DM and its complications.