High Glucose Concentrations Increase Endothelial Cell Permeability via Activation of Protein Kinase Cα

Hempel, Albrecht; Maasch, Christian; Heintze, Ute; Lindschau, Carsten; Dietz, Rainer; Luft, Friedrich C.; Haller, Hermann

doi:10.1161/01.res.81.3.363

Cited by 203 publications

(172 citation statements)

References 39 publications

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“…In addition, studies in non-diabetic humans have consistently shown that acute hyperglycemia impairs endothelium-dependent vasodilation. 28,32,33 Potential mechanisms for glucose-mediated endothelial dysfunction may include reduced nitric oxide bioavailability caused by increased formation of reactive oxygen intermediates, 34,35 glucose auto-oxidation, 36 activation of protein kinase C, 37,38 formation of advanced glycosylation end products, 39 decreased nitric oxide synthase expression, 40 and direct chemical inactivation of nitric oxide by glucose. 41 Acute oxidant stress possibly plays a role in glucosemediated endothelial dysfunction, because hyperglycemia induced impairment in endothelial function can be reversed by pretreatment with antioxidant vitamins.…”

Section: Discussionmentioning

confidence: 99%

Weight Reduction With Very-Low-Caloric Diet and Endothelial Function in Overweight Adults: Role of Plasma Glucose

Raitakari

Ilvonen

Ahotupa

et al. 2004

ATVB

176

119

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Objective-Obesity is associated with endothelial dysfunction that may contribute to the development of atherosclerosis.We studied whether weight reduction improves endothelial function in overweight individuals. Methods and Results-Flow-mediated endothelium-dependent vasodilation of the brachial artery was measured in 67 adults (age: 46Ϯ7 years, body mass index: 35.2Ϯ5.4 kg/m 2 ) before and after a 6-week weight reduction program induced by very-low-calorie diet (daily energy: 580 kcal/2.3 MJ). Caloric restriction reduced body weight from 101Ϯ18 to 90Ϯ17 kg. Flow-mediated vasodilation increased from 5.5%Ϯ3.7 to 8.8%Ϯ3.7% (PϽ0.0001). Nitrate-mediated vasodilation was not significantly affected. The improvement in flow-mediated dilation was associated with the reduction in plasma glucose concentration (Pϭ0.0003). This relationship was independent of changes in weight, serum lipids, oxidized LDL, C-reactive protein, adiponectin, blood pressure, and insulin. Key Words: endothelium Ⅲ obesity Ⅲ risk factors Ⅲ glucose Ⅲ weight reduction T he vascular endothelium plays an important role in the regulation of arterial tone, thrombosis, and inflammation. Endothelial dysfunction may predispose arteries to the development of atherosclerotic lesions and is pathophysiologically linked to acute cardiovascular syndromes. 1 A common condition associated with endothelial dysfunction is obesity. Endothelial-dependent vascular responses to both agoniststimulated 2,3 and flow-mediated vasodilation 4 have been shown to be blunted in obese individuals. The mechanisms of obesity-induced endothelial dysfunction may be multifactorial, because excess adipose tissue induces several metabolic changes that may interfere with normal endothelial function. These may include dyslipidemia, elevated blood pressure, increased inflammation, oxidative stress, and changes in glucose metabolism. 5 Although weight reduction is known to reduce several of these risk factors for endothelial dysfunction, it is inadequately known whether endothelial function can be improved by reducing weight. We hypothesized that weight loss induced by very-low-calorie diet would enhance flow-mediated endothelium-dependent vasodilation in overweight adults. To gain insight for possible mechanisms of weight-loss-mediated changes in flow-mediated dilation, we also measured changes in several potential biochemical determinants of endothelial function. Conclusions-Weight Methods SubjectsWe recruited overweight (body mass index Ͼ27kg/m 2 ) men and women from an occupational health service clinic. The exclusion criteria included diabetes, pregnancy, gout, gall stone disease, alcohol/drug abuse, liver/kidney disorder, psychiatric disorder, and use of cholesterol lowering medication.Of the 74 subjects enrolled, 47 women and 20 men completed the 6-week program (9.5% dropout rate). Sixteen women were postmenopausal (2 using hormone replacement therapy), 19 subjects had treatment for hypertension, and there were 7 smokers and 13 ex-smokers. Most participants (65%) were sedentary, engag...

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Section: Discussionmentioning

confidence: 99%

Weight Reduction With Very-Low-Caloric Diet and Endothelial Function in Overweight Adults: Role of Plasma Glucose

Raitakari

Ilvonen

Ahotupa

et al. 2004

ATVB

176

119

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“…These antibodies have been shown to react with the specific PKC isoforms in porcine aortic endothelial cells and in airway and coronary smooth muscle cells. [23][24][25][26] The specificity of the antibodies was confirmed by the observation that the peptide controls were successful only with the peptide to which the antibodies were raised and not with other sequences of the PKC molecule. To maintain constant labeling conditions, we used the same anti-PKC antibody titer (1:500) and protein concentration (10 g) in all tissue samples.…”

Section: Immunoblottingmentioning

confidence: 94%

Endothelin-1 Enhances Eicosanoids-Induced Coronary Smooth Muscle Contraction by Activating Specific Protein Kinase C Isoforms

2001

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Abstract-Endothelin-1 (ET-1), a potent vasoconstrictor, has been implicated in the pathogenesis of coronary vasospasm by enhancing coronary vasoconstriction to vasoactive eicosanoids; however, the cellular mechanisms involved are unclear. We investigated whether physiological concentrations of ET-1 enhance coronary smooth muscle contraction to vasoactive eicosanoids by activating specific protein kinase C (PKC) isoforms. Cell contraction was measured in single smooth muscle cells isolated from porcine coronary arteries, intracellular free Ca 2ϩ ([Ca 2ϩ ] i ) was measured in fura-2-loaded cells, and the cytosolic and particulate fractions were examined for PKC activity and reactivity with isoform-specific anti-PKC antibodies using Western blots. In Hanks -7 mol/L) caused cell contraction (10%) and enhanced PGF 2␣ contraction (33%) with no additional increase in [Ca 2ϩ ] i (115Ϯ7 nmol/L). The ET-1-induced enhancement of PGF 2␣ contraction was inhibited by Gö6976 (10 -6 mol/L), an inhibitor of Ca 2ϩ -dependent PKC isoforms. Both ET-1 and PDBu caused an increase in PKC activity in the particulate fraction and a decrease in the cytosolic fraction and increased the particulate/cytosolic PKC activity ratio. Western blots revealed the Ca 2ϩ -dependent ␣-PKC and the Ca 2ϩ -independent ␦-, ⑀-, and -PKC isoforms. In resting tissues, ␣-and ⑀-PKC were mainly cytosolic, ␦-PKC was mainly in the particulate fraction, and -PKC was equally distributed in the cytosolic and particulate fraction. ET-1 (10 pmol/L) alone or PDBu (10 -7 mol/L) alone caused translocation of ⑀-PKC from the cytosolic to the particulate fraction, localized ␦-PKC more in the particulate fraction, but did not change the distribution of -PKC. PGF 2␣ (10 -7 mol/L) alone did not change PKC activity. In tissues pretreated with ET-1 or PDBu, PGF 2␣ caused additional increases in ␣-PKC activity. Thus, the enhancement of PGF 2␣ -induced coronary smooth muscle contraction by physiological concentrations of ET-1 involves activation and translocation of ␣-PKC in addition to ␦-and ⑀-PKC isoforms, and this may represent one possible cellular mechanism by which ET-1 could enhance coronary vasoconstriction to vasoactive eicosanoids in coronary vasospasm.

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“…We selected antisense ODNs against the 3Ј-untranslated region [as ␣ (1)] and against the AUG start codon [as ␣ (2)] derived from the rat PKC-␣ sequence (accession number X07286). 30 The antisense sequence used for PKC-␣(1) was TCT TTT GTT GAG TTT CA and for PKC-␣(2) was CAG CCA TTG TCC CCC CCA AC. The sense ODN sequence, a reverse ODN sequence, and a scrambled version were used as controls.…”

Section: Antisense Experimentsmentioning

confidence: 99%

“…29 In addition, we reported that high glucose increases endothelial cell permeability via PKC-␣ and that PKC-␣ is important in vascular smooth muscle cell (VSMC) differentiation. 30,31 We now tested whether or not PKC-␣ mediates glucoserelated effects on TGF-␤1 and its receptors.…”

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confidence: 99%

Glucose-Induced TGF-β1 and TGF-β Receptor-1 Expression in Vascular Smooth Muscle Cells Is Mediated by Protein Kinase C-α

Lindschau

Quass²,

Menne³

et al. 2003

Hypertension

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Abstract-Sclerosis and increased matrix expression in diabetes are mediated by glucose-induced transforming growth factor (TGF)-␤1 expression. The intracellular effects of high glucose occur at least in part by way of protein kinase C (PKC). We previously described a role for PKC-␣ in glucose-induced permeability. We now investigated the hypothesis that glucose-induced expression of TGF-␤1 and its receptors (TGF-␤-R1 and -R2) are mediated by activation of this PKC isoform. TGF-␤1 and TGF-␤-R expressions were determined in vascular smooth muscle cells (VSMCs) by immunocytochemistry and Western blotting. PKC isoforms were assessed by confocal microscopy. PKC isoforms were inhibited with antisense oligodeoxynucleotides. PKC-␣ was upregulated by overexpression or microinjection. High glucose (20 mmol/L) increased VSMC TGF-␤1 and TGF-␤-R1 expression but not TGF-␤-R2 expression. PKC inhibitors and specific PKC-␣ downregulation by antisense treatment prevented this effect, whereas antisense treatment against PKC-␤, -⑀, and -had no influence. PKC-␣ overexpression increased TGF-␤1 and TGF-␤-R1 expression but not TGF-␤-R2 expression. PKC-␣ microinjection into individual VSMCs also increased TGF-␤1 and TGF-␤-R immunofluorescence. Last, VSMCs from PKC-␣-deficient mice did not respond to high glucose compared with VSMCs from wild-type mice. We propose that high glucose-induced TGF-␤1 and TGF-␤-R1 expression is mediated by PKC-␣. Our findings suggest an autocrine feedback mechanism and a possible role for PKC-␣ in diabetic vascular disease. Key Words: glucose Ⅲ growth substances Ⅲ protein kinases Ⅲ diabetes Ⅲ muscle, vascular, smooth Ⅲ atherosclerosis R enal hypertrophy, basement membrane thickening, and extracellular matrix accumulation characterize diabetic nephropathy. 1 Several cytokines with fibrogenic potential contribute to this, particularly transforming growth factor (TGF)-␤1. 2 TGF-␤1 increases matrix synthesis, inhibits matrix degradation, upregulates adhesion molecules, and enhances chemoattraction. 3,4 The possible importance of TGF-␤1 in diabetic nephropathy has been demonstrated in vitro by glucose-induced upregulation of this cytokine in different cell types. 5-13 Increased TGF-␤1 expression has also been demonstrated in diabetic animal models and human patients. 14,15 TGF-␤ binds specific serine/threonine kinase type I and type II receptors. The receptors form heteromeric cell surface complexes with TGF-␤. 16,17 The type II receptor determines ligand specificity, whereas the type I receptor interacts with the type II receptor and might not have a specific ligand. The type II receptor, likely in conjunction with the type I receptor, is probably required for the antiproliferative effect, whereas the type I receptor is the probable mediator of extracellular gene expression. 16,17 High glucose upregulates TGF-␤1 receptors in vitro and in vivo. 18,19 Hyperglycemia might mediate the effect of protein kinase C (PKC) activation. 20 -24 PKC consists of several isoforms with distinct cellular functions and different ex...

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High Glucose Concentrations Increase Endothelial Cell Permeability via Activation of Protein Kinase Cα

Cited by 203 publications

References 39 publications

Weight Reduction With Very-Low-Caloric Diet and Endothelial Function in Overweight Adults: Role of Plasma Glucose

Weight Reduction With Very-Low-Caloric Diet and Endothelial Function in Overweight Adults: Role of Plasma Glucose

Endothelin-1 Enhances Eicosanoids-Induced Coronary Smooth Muscle Contraction by Activating Specific Protein Kinase C Isoforms

Glucose-Induced TGF-β1 and TGF-β Receptor-1 Expression in Vascular Smooth Muscle Cells Is Mediated by Protein Kinase C-α

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