Role of Superoxide Anions in Changes of Endothelial Vasoactive Response during Acute Hyperglycemia

Graier, Wolfgang F.; Posch, Karla; Wascher, Thomas C.; Kostner, Gert M.

doi:10.1055/s-2007-979113

Cited by 55 publications

(39 citation statements)

References 5 publications

(6 reference statements)

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“…3) could reorganise the architecture of the cytoskeleton, modulate Ca 2+ -sensitive/-activated transcription factors and signal cascade enzymes resulting in altered gene expression [136,190,191,192] (for review see [135]). In line with these data in beta cells, in endothelial cells the 54,193,194,195,196,197]. Thereby, the impact of Ca 2+ on gene expression exceeded its role in the nuclear envelope, where Ca 2+ is essential for modulating immediate early genes by modulating the DNA-binding of transcription factors (e. g. cAMP-responsive element binding protein CREB [191,192,198,199,200]).…”

Section: Nomentioning

confidence: 54%

Vascular targets of redox signalling in diabetes mellitus

2002

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There is overwhelming evidence for an involvement of reactive oxygen species (ROS) in the pathogenesis of diabetes-associated vascular complications. However, neither the exact source of the ROS initiating cascades leading to cell dysfunction in diabetes nor their chemical nature is fully understood. Furthermore, despite our knowledge of the crucial role of ROS in diabetes, little is known about the actual targets and the molecular consequences of the interaction of ROS with cellular signalling pathways.Therefore, we aim to provide an overview of ROS (i. e. O 2 · , NO · , ONOO  and H 2 O 2 ) and their vascular sources in diabetes and to summarise recent knowledge on the mechanisms underlying increased ROS production within the vascular wall. In addition, possible targets of diabetes and ROS within the vasculature are discussed. These include, the effects of ROS on small guanine nucleotide binding proteins, the cytoskeleton, protein kinases (e. g. tyrosine kinases), metalloproteinases, ion homeostasis and transcriptional regulation.Such analysis makes it clear that the generation of ROS could affect a large number of various signalling pathways and proteins. Thus, a better knowledge of the functional diversity and pathological consequences of each individual pathway activated by ROS is essential to understand the mechanisms of diabetesassociated vascular complications. [Diabetologia (2002) 45:476±494]

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Section: Nomentioning

confidence: 54%

Vascular targets of redox signalling in diabetes mellitus

2002

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“…Notably, endothelial Ca 2+ signalling has been shown to be a suitable marker for cell dysfunction initiated by a variety of stimuli such as E. coli lipopolysaccharides (LPS; [19]), peroxides [20,21,22], oxidized low density lipoprotein [23], streptozotocininduced diabetes [24,25] and hyperglycaemia [10,11,26]. The latter was causally linked to generation of · O 2 -in EC [10,27]. In line with these reports, the interaction of EC with high D-glucose pre-exposed SMC augmented the increase in cytosolic Ca 2+ in response to bradykinin.…”

Section: Discussionmentioning

confidence: 99%

Intercellular signalling within vascular cells under high D-glucose involves free radical-triggered tyrosine kinase activation

et al. 2003

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Aims/hypothesis. Diabetes mellitus is associated with endothelial dysfunction in human arteries due to the release of superoxide anions ( · O 2 -) that was found to occur predominantly in smooth muscle cells (SMC). This study was designed to elucidate the impact of high glucose concentration mediated radical production in SMC on EC. Pre-treatment of vascular SMC with increased D-glucose enhanced release of · O 2 -. Methods. Microscope-based analyses of intracellular free Ca 2+ concentration (fura-2), immunohistochemistry (f-actin) and tyrosine kinase activity were performed. Furthermore, RT-PCR and Western blots were carried out. Results. Interaction of EC with SMC pre-exposed to high glucose concentration yielded changes in endothelial Ca 2+ signalling and polymerization of f-actin in a concentration-dependent and superoxide dismutase (SOD) sensitive manner. This interaction activated endothelial tyrosine kinase(s) but not NFκB and AP-1, while SOD prevented tyrosine kinase stimulation but facilitated NFκB and AP-1 activation. Erbstatin, herbimycin A and the src family specific kinase inhibitor PP-1 but not the protein kinase C inhibitor GF109203X prevented changes in endothelial Ca 2+ signalling and cytoskeleton organization induced by pre-exposure of SMC to high glucose concentration. Adenovirus-mediated expression of kinase-inactive c-src blunted the effect of pre-exposure of SMC to high glucose concentration on EC. Conclusions/interpretation. These data suggest that SMC-derived · O 2 -alter endothelial cytoskeleton organization and Ca 2+ signalling via activation of c-src. The activation of c-src by SMC-derived radicals is a new concept of the mechanisms underlying vascular dysfunction in diabetes. [Diabetologia (2003) 46:773-783]

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“…Studies of endothelial cells treated with high glucose in culture showed that high glucose-induced superoxide formation leads to an increase in intracellular calcium that activates endothelial NOS (NOS3) to form NO, but also causes NOS3 "uncoupling" to generate superoxide as well as NO (Fig. 10) (El-Remessy, 2003a;Graier et al, 1999;Graier et al, 1997;Graier et al, 1996) resulting in peroxynitrite formation. Research demonstrating increased levels of the peroxynitrite biomarker nitrotyrosine in retinas of diabetic patients and experimental animal models supports this concept and implies a role for peroxynitrite in the development of diabetic complications (Abu El-Asrar et al, 2004;Du et al, 2002;ElRemessy, 2003b;Kowluru and Odenbach, 2004;Obrosova et al, 2005).…”

Section: Oxidative Stress and Diabetic Retinopathymentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

614

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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Role of Superoxide Anions in Changes of Endothelial Vasoactive Response during Acute Hyperglycemia

Cited by 55 publications

References 5 publications

Vascular targets of redox signalling in diabetes mellitus

Vascular targets of redox signalling in diabetes mellitus

Intercellular signalling within vascular cells under high D-glucose involves free radical-triggered tyrosine kinase activation

Vascular endothelial growth factor in eye disease

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