Tetrahydrobiopterin impairs the action of endothelial nitric oxide <i>via</i> superoxide derived from platelets

Tajima, Masamichi; Sakagami, Hiroshi

doi:10.1038/sj.bjp.0703648

Cited by 17 publications

(15 citation statements)

References 43 publications

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“…Isolated vessel segments in an organ bath set-up suspended between two wires are not exposed to pulsatile forces, which stimulate basal NO production in vivo [38]. However, previous work [39,40] has shown that basal production of NO occurs under resting conditions, and this was also found to be the case in the present study.…”

Section: Discussionmentioning

confidence: 43%

Chylomicron-remnant-like particles inhibit the basal nitric oxide pathway in porcine coronary artery and aortic endothelial cells

et al. 2003

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The effects of chylomicron remnants on the activity of basally produced nitric oxide (NO) from porcine coronary artery rings and porcine aortic endothelial cells were studied by investigating the effects of chylomicron-remnant-like particles (CMR-LPs) containing porcine apolipoprotein E on the vessel tone of porcine coronary arteries and on cGMP release by aortic endothelial cells. CMR-LPs were oxidized by incubation with CuSO(4) (10 microM) for 18 h at 37 degrees C. N (omega)-nitro-L-arginine (L-NOARG) and oxidized CMR-LPs (oxCMR-LPs), but not native CMR-LPs, increased the vessel tone of static porcine coronary artery rings (increase in tone as a percentage of the tone induced by depolarizing Krebs-Henseleit solution: L-NOARG, 14.24 +/- 2.09; oxCMR-LPs, 4.98 +/- 0.88; and native CMR-LPs, 0.47 +/- 0.21). L-NOARG, endothelium removal and oxCMR-LPs also all significantly increased the maximum relaxation of the vessels to S -nitroso- N -acetyl-DL-penicillamine. In addition, oxCMR-LPs reduced the amounts of cGMP released by porcine aortic endothelial cells into the culture medium from 116 +/- 12.0 to 84.2 +/- 11.6 fmol/microg of cellular protein, mimicking the effects of L-NOARG. These results indicate that oxCMR-LPs, but not native CMR-LPs, inhibit the activity, production or release of NO from unstimulated porcine coronary and aortic endothelial cells. oxCMR-LPs mimicked the addition of L-NOARG and endothelium removal in these experimental systems, suggesting that the lipoproteins were interfering with the L-arginine/NO pathway. This study provides further evidence to support a role of chylomicron remnants in the development of atherosclerosis.

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Section: Discussionmentioning

confidence: 43%

Chylomicron-remnant-like particles inhibit the basal nitric oxide pathway in porcine coronary artery and aortic endothelial cells

et al. 2003

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“…50 There is accumulating evidence that platelet-derived O 2 Ϫ is a functionally relevant scavenger of platelet-derived NO, which inhibits the anti-aggregatory effects of platelet-derived NO. 45,61 In accordance with this, GPIIb/IIIa inhibitors decrease platelet O 2 Ϫ release and enhance platelet NO release concomitantly. 61 Some of these observations also indicate that an effect of plateletderived ROS on platelet aggregation may play a prominent role in a late phase of aggregation.…”

Section: Role Of Ros In Platelet Signalingmentioning

confidence: 69%

“…43 Inhibition of platelet O 2 Ϫ formation by diphenylene iodonium chloride has been shown independently by several groups. 44,45 The first direct evidence for the expression of a platelet NAD(P)H-oxidase was presented by Seno et al, who detected p22 phox and p67 phox , 2 subunits of the NAD(P)Hoxidase enzyme (there are at least 5 known subunits), in platelet lysates. 46 The expression of a platelet isoform of NAD(P)H-oxidase was further underpinned by detection of the gp91 phox and p47 phox subunits.…”

Section: Role Of Platelet-derived Rosmentioning

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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“…[4][5][6] ROSs may regulate platelet function by decreasing NO bioavailability because ROSs scavenge platelet or endothelium-derived nitric oxide (NO). [7][8][9] However, it is still not clear whether the only possible mechanism for the regulation of platelet activation by ROSs is due to decreased NO bioavailability or perhaps due to a direct role of ROSs in the control of platelet functions. 1 Because the source of intracellular ROS production as well as the potential role of ROSs in platelets are not well defined, it was our goal (1) to determine which platelet agonists cause ROS production; (2) to ascertain possible sources of ROSs; (3) to test if platelet ROSs affect platelet function by altering integrin activation or platelet secretion; and (4) to test the hypothesis that inhibition of ROSs in platelets increases platelet NO/cyclic guanosine monophosphate (NO/cGMP) levels and vasodilator-stimulated phosphoprotein (VASP) phosphorylation and thus inhibits platelets.…”

Section: Introductionmentioning

confidence: 99%

Platelet NAD(P)H-oxidase–generated ROS production regulates αIIbβ3-integrin activation independent of the NO/cGMP pathway

Begonja

Gambaryan

Geiger

et al. 2005

Blood

203

160

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Platelets play a crucial role in the physiology of primary hemostasis and pathophysiologic processes such as arterial thrombosis. Accumulating evidence suggests a role of reactive oxygen species (ROSs) in platelet activation. Here we show that platelets activated with different agonists produced intracellular ROSs, which were reduced by reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitors and superoxide scavengers. In addition, we demonstrate that ROSs produced in platelets significantly affected ␣IIb␤3 integrin activation but not alpha and dense granule secretion and platelet shape change. Thrombin-induced integrin ␣IIb␤3 activation was significantly decreased after pretreatment of platelets with NAD (

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Tetrahydrobiopterin impairs the action of endothelial nitric oxide via superoxide derived from platelets

Cited by 17 publications

References 43 publications

Chylomicron-remnant-like particles inhibit the basal nitric oxide pathway in porcine coronary artery and aortic endothelial cells

Chylomicron-remnant-like particles inhibit the basal nitric oxide pathway in porcine coronary artery and aortic endothelial cells

Reactive Oxygen Species

Platelet NAD(P)H-oxidase–generated ROS production regulates αIIbβ3-integrin activation independent of the NO/cGMP pathway

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