Differential regulation of protein kinase C and (Na,K)-adenosine triphosphatase activities by elevated glucose levels in retinal capillary endothelial cells.

Lee, T S; MacGregor, Leslie C.; Fluharty, Steven J.; King, George L.

doi:10.1172/jci113889

Cited by 138 publications

(72 citation statements)

References 23 publications

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“…There is some evidence that high glucose can lead to an increased formation of diacylglycerol and thereby, to an activation of protein kinase [27,28]. Furthermore, several authors have described that protein kinase C (PKC) may be involved in regulation of apoptosis [10±15], although the direction of the effect varies in the different types of cells.…”

Section: Discussionmentioning

confidence: 99%

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

Sui

Stockklauser-Färber

et al. 1998

Diabetologia

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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)

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Section: Discussionmentioning

confidence: 99%

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

Sui

Stockklauser-Färber

et al. 1998

Diabetologia

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“…Activation of PKC has also been hypothesized to play a role in glucose toxicity and the mediation of complications in diabetes. This is based on the observations that PKC activity is induced in cells exposed to high concentrations of glucose, possibly through the increased accumulation of diacylglycerol, an activator of PKC (32)(33)(34). We have found, however, that in these cells phorbol ester stimulates TGFa promoter activity minimally compared with the stimulation by sugar (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells.

McClain

Paterson

Roos

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

178

110

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We have investigated the regulation of the expression of two growth factors found in vascular smooth muscle, transforming growth factor a (TGFa) and basic fibroblast growth factor (bFGF). Cells cultured in medium containing 30 mM glucose exhibited a 2-fold increase in TGFa mRNA and a 3-fold increase in bFGF mRNA compared with cells grown in normal (5.5 mM) glucose. Glucosamine was more potent than glucose, leading to a 6-fold increase in TGFa mRNA. TGFa protein levels were also increased by glucosamine treatment, and the predominant species present was the membrane-bound precursor form of TGFa. To examine further the regulation of growth factors by sugars, cultured rat aortic smooth muscle cells were transfected with a plasmid construct consisting of a 1.2-kilobase-pair fragment of the TGFa promoter linked to a luciferase reporter gene. Increasing the concentration ofglucose in the culture medium from 5.5 mM to 30 mM led to a rapid, 1.7-fold increase in the activity of the TGFa promoter. Glucosamine was much more potent than glucose in this stimulation, with 2 mM gluamine causing a 12-fold increase in TGFa promoter activity. Insulin had no effect on luciferase activity in either the presence or the absence of added sugars. The glucose response element of the TGFa gene maps to a 130-base-pair segment that includes three potential binding sites for the transcription factor Spl. We conclude that high glucose concentrations such as are reached in diabetes mellitus can stimulate the transcription of the genes for growth factors in vascular smooth muscle cells. This signaling pathway apparently involves the metabolism of glucose to glucosamine. This effect could be representative of nutritional regulation of a family of genes and could contribute to the toxicity of hyperglycemia and the vascular complications of diabetes.Vascular smooth muscle cell proliferation is an early event in the pathogenesis of atherosclerosis, and growth factors have been hypothesized to play an important role in the control of this process (1). For example, platelet-derived growth factor is expressed in atherosclerotic lesions and is found in macrophages in all phases ofthe development of those lesions (2). Growth factors synthesized by the vascular smooth muscle cells themselves may also be involved in the pathogenesis of vascular disease. Thus, the exposure of vascular smooth muscle cells to growth factors could be determined by the plasma concentration of a growth factor, by delivery from blood-derived cells, or by the production rate of the growth factor by cells within the vessel wall. To examine whether the synthesis of growth factors might be sensitive to environmental conditions, we studied two growth factors known to be expressed in vascular smooth muscle cells, transforming growth factor a (TGFa; refs. 3 and 4) and basic fibroblast growth factor (bFGF; refs. 5 and 6). In addition, because the promoter for the TGFa gene has been cloned and characterized (7, 8), we studied in more detail the transcriptional regulation of the ...

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“…These include abnormalities in signal transduction, reduced synthesis of NO, accelerated inactivation of nitric oxide, and generation and release of competing vasoconstrictor substances. Faulty signal transduction has been variably attributed to decreased expression of inhibitory G proteins, reduced phosphoinositol metabolism, and increased activation of protein kinase C [Gawler et al, 1987;Lee et al, 1989]. Abnormalities in the endothelial milieu might hasten the inactivation of nitric oxide.…”

Section: Microvascular Dysfunction In Type-1 Diabetes Mellitusmentioning

confidence: 99%

Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: Role of insulin and C‐peptide

Joshua

Zhang

Falcone

et al. 2005

J of Cellular Biochemistry

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Complications associated with insulin-dependent diabetes mellitus (type-1diabetes) primarily represent vascular dysfunction that has its origin in the endothelium. While many of the vascular changes are more accountable in the late stages of type-1diabetes, changes that occur in the early or initial functional stages of this disease may precipitate these later complications. The early stages of type-1diabetes are characterized by a diminished production of both insulin and C-peptide with a significant hyperglycemia. During the last decade numerous speculations and theories have been developed to try to explain the mechanisms responsible for the selective changes in vascular reactivity and/or tone and the vascular permeability changes that characterize the development of type-1diabetes. Much of this research has suggested that hyperglycemia and/or the lack of insulin may mediate the observed functional changes in both endothelial cells and vascular smooth muscle. Recent studies suggest several possible mechanisms that might be involved in the observed decreases in vascular nitric oxide (NO) availability with the development of type-1 diabetes. In addition more recent studies have indicated a direct role for both endogenous insulin and C-peptide in the amelioration of the observed endothelial dysfunction. These results suggest a synergistic action between insulin and C-peptide that facilitates increase NO availability and may suggest new clinical treatment modalities for type-1 diabetes mellitus.

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Differential regulation of protein kinase C and (Na,K)-adenosine triphosphatase activities by elevated glucose levels in retinal capillary endothelial cells.

Cited by 138 publications

References 23 publications

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

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

Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells.

Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: Role of insulin and C‐peptide

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