Platelet glutathione and thromboxane synthesis in diabetes

Thomas, G.; Skrinska, Victor; Lucas, F. V.; Schumacher, O. Peter

doi:10.2337/diabetes.34.10.951

Cited by 33 publications

(16 citation statements)

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“…In contrast to previous investigations that demonstrated enhanced release of TXA2 from glutathione-deficient platelets (34,35), platelets treated with dehydroepiandrosterone did not have augmented synthesis of TXA2 as measured by iTXB2 production. We additionally did not demonstrate that dehydroepiandrosterone-treated platelets generated iTXB2 after stimulation with purine and xanthine oxidase in concentrations instilled in the isolated lung studies.…”

Section: Discussioncontrasting

confidence: 52%

“…The contribution of cyclooxygenase-dependent products, such as endoperoxides or TXA2, was explored because they are potent vasoconstrictors at the postcapillary level (32,33). Also, an inverse relationship exists between platelet glutathione content and the capacity ofplatelets to synthesize TXA2 (34,35). Inhibition of platelet cyclooxygenase by acetylsalicylate in G-6-PD-inhibited platelets prevented the PA pressor response and augmentation of lung injury observed after the infusion of xanthine oxidase and G-6-PD-inhibited platelets with intact cyclooxygenase enzyme.…”

Section: Discussionmentioning

confidence: 99%

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Human platelets modulate edema formation in isolated rabbit lungs.

Heffner¹,

Cook²,

Halushka³

1989

J. Clin. Invest.

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The role of platelet glucose-6-phosphate dehydrogenase (G-6-PD) in mediating the effects of human platelets on oxidant-induced edema in the isolated perfused rabbit lung was investigated using dehydroepiandrosterone, a specific steroidal inhibitor of G-6-PD. Xanthine oxidase (0.003 and 0.012 U/ml) caused lung edema that was attenuated by coinfusion of washed human platelets. Platelets that were incubated with DEA to inhibit G-6-PD activity augmented xanthine oxidase-induced lung edema and pulmonary hypertension at both doses of xanthine oxidase. Infusion of papavarine to maintain stable pulmonary artery (PA) pressures, incubation of G-6-PD-inhibited platelets with acetylsalicylate, or infusion of a thromboxane-prostaglandin endoperoxide receptor site antagonist, SQ 29548, into the lung perfusate prevented augmentation of lung edema and the PA pressor response by G-6-PD-inhibited platelets. It was concluded that antioxidant-intact platelets attenuate oxidant-induced lung edema by preventing increased membrane permeability, and that G-6-PD-inhibited platelets augment lung edema through hydrostatic mechanisms mediated by release of platelet cyclooxygenase products.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Human platelets modulate edema formation in isolated rabbit lungs.

Heffner¹,

Cook²,

Halushka³

1989

J. Clin. Invest.

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“…Glutathione (GSH), an important intracellular antioxidant, is depleted in erythrocytes [1], plasma [2], leucocytes [3], and platelets from human diabetic patients [4] and in endothelial cells from diabetic rabbits [5]. The changes in GSH levels, which result in an oxidant/prooxidant imbalance, may predispose the cells to oxidantinduced damage and diabetic complications.…”

Section: Introductionmentioning

confidence: 99%

Restoration of glutathione levels in vascular smooth muscle cells exposed to high glucose conditions

Powell

Nally

McMaster

et al. 2001

Free Radical Biology and Medicine

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Abstract-Hyperglycemia-induced oxidative stress may play a key role in the pathogenesis of diabetic vascular disease. The purpose of this study was to determine the effects of glucose on levels of glutathione (a major intracellular antioxidant), the expression of ␥-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione de novo synthesis), and DNA damage in human vascular smooth muscle cells in vitro. High glucose conditions and buthionine sulphoximine, an inhibitor of ␥-glutamylcysteine synthetase, reduced intracellular glutathione levels in vascular smooth muscle cells. This reduction was accompanied by a decrease in the mRNA expression of both subunits of ␥-glutamylcysteine synthetase as well as an increase in DNA damage. In high glucose conditions, incubation of the vascular smooth muscle cells with ␣-lipoic acid and L-cystine restored glutathione levels. We suggest that the decrease in GSH levels seen in high glucose conditions is mediated by the availability of cysteine (rate-limiting substrate in de novo glutathione synthesis) and the gene expression of the ␥-glutamylcysteine synthetase enzyme. Glutathione depletion is associated with an increase in DNA damage, which can be reduced when glutathione levels are restored.

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“…71 Consequently, platelet supplementation with GSH decreases platelet aggregation in vitro. [72][73][74] Further, N-acetyl-Lcysteine, which is capable of restoring intracellular thiol stores by shifting the redox balance in favor of GSH, inhibits platelet aggregation and potentiates the antiplatelet effects of NO, 75 underscoring the critical role for the platelets' intracellular redox state.…”

Section: Role Of Ros In Platelet Signalingmentioning

confidence: 99%

Reactive Oxygen Species

Krötz

Sohn

Pohl

2004

ATVB

406

122

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Abstract-Platelets participate not only in thrombus formation but also in the regulation of vessel tone, the development of atherosclerosis, angiogenesis, and in neointima formation after vessel wall injury. It is not surprising, therefore, that the platelet activation cascade (including receptor-mediated tethering to the endothelium, rolling, firm adhesion, aggregation, and thrombus formation) is tightly regulated. In addition to already well-defined platelet regulatory factors, such as nitric oxide (NO), prostacyclin (PGI 2 ), and adenosine, reactive oxygen species (ROS) participate in the regulation of platelet activation. Although exogenously derived ROS are known to affect the regulation of platelet activation, recent data suggest that the platelets themselves generate ROS. Intracellular ROS signaling in activated platelets could be of significant relevance after transient platelet contact with the vessel wall, during the recruitment of additional platelets, and in thrombus formation. This review discusses the potential cellular and enzymatic sources of ROS in platelets, their molecular mechanisms of action in platelet activation, and summarizes in vitro and in vivo evidence for their physiological and potential therapeutic relevance. Key Words: platelets Ⅲ reactive oxygen species Ⅲ NAD(P)H-oxidase Ⅲ aggregation Ⅲ adhesion Ⅲ thrombus formation P latelet interaction with the vessel wall serves numerous physiological and pathophysiological functions. This is reflected by the fact that platelets release growth factors, 1 lipid mediators, 2,3 and cytokines. 4 Consequently, the regulation of platelet activity plays a role not only for thrombus formation and the regulation of vascular tone 5 but also for the vascular pathophysiology of angiogenesis and inflammation. Moreover, platelets participate in the development of atherothrombotic disease by promoting atherosclerotic lesion 6 and neointima formation. 7 Not surprisingly, the activation of platelets is regulated and modulated by numerous factors, blood-borne and cell-derived. Most of these factors are relatively well-characterized. 8 However, in recent time, several publications have suggested that reactive oxygen species (ROS) represent a new modulator of platelet activity. It has been known for some time that ROS exert critical regulatory functions within the vascular wall and it is therefore plausible that platelets represent a relevant target for their action.Within the vessel wall (where endothelial cells, vascular smooth muscle cells, and fibroblasts express a variety of ROS-generating enzymes), there is a constant, low-quantity flux of ROS. It is already established that enhanced ROS release from the vascular wall can indirectly affect platelet activity by scavenging nitric oxide (NO), thereby decreasing the antiplatelet properties of the endothelium. 9 In addition to their exposure to ROS derived from the vascular wall, platelets themselves also can generate ROS, and there is some evidence for a more direct role of ROS in the control of platelet activi...

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Platelet glutathione and thromboxane synthesis in diabetes

Cited by 33 publications

References 0 publications

Human platelets modulate edema formation in isolated rabbit lungs.

Human platelets modulate edema formation in isolated rabbit lungs.

Restoration of glutathione levels in vascular smooth muscle cells exposed to high glucose conditions

Reactive Oxygen Species

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