S‐nitrosothiols as selective antithrombotic agents – possible mechanisms

Gordge, Michael P.; Xiao, Fang

doi:10.1111/j.1476-5381.2010.00670.x

Cited by 19 publications

(16 citation statements)

References 108 publications

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“…We have previously argued that the former mechanism is more important in platelets [15] and the results of the present study are consistent with this hypothesis. We suggest that the platelet selective actions of GSNO result from platelet surface thiol isomerases metabolising GSNO more rapidly than the endothelial lining of the blood vessel wall, allowing anti-platelet action of NO to occur without significant NO delivery to vascular smooth muscle to bring about vasodilation.…”

Section: Discussionsupporting

confidence: 93%

Cell surface thiol isomerases may explain the platelet-selective action of S-nitrosoglutathione

Xiao

Gordge

2011

Nitric Oxide

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S-nitrosoglutathione (GSNO) at low concentration inhibits platelet aggregation without causing vasodilation, suggesting platelet-selective nitric oxide delivery. The mechanism of this selectivity is unknown, but may involve cell surface thiol isomerases, in particular protein disulphide isomerase (csPDI) (EC 5.3.4.1). We have now compared csPDI expression and activity on platelets, endothelial cells and vascular smooth muscle cells, and the dependence on thiol reductase activity of these cell types for NO uptake from GSNO.csPDI expression was measured by flow cytometry and its reductase activity using the pseudosubstrate dieosin glutathione disulphide. This activity assay was adapted and validated for 96-well plate format. Flow cytometry revealed csPDI on all three cell types, but percentage positivity of expression was higher on platelets than on vascular cells. Consistent with this, thiol isomerase-related reductase activity was higher on platelets (P < 0.01), and cellular activation (with either phorbol myristate acetate or ionomycin) increased csPDI activity on both platelets and smooth muscle cells, but not on endothelium. Intracellular NO delivery from GSNO was greater in platelets than in vascular cells (P < 0.002), and was more sensitive to thiol isomerase inhibition using phenylarsine oxide (P < 0.05).Increased surface thiol isomerase activity on platelets, compared with cells of the vascular wall, may explain the platelet-selective actions of GSNO and help define its antithrombotic potential.

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Section: Discussionsupporting

confidence: 93%

Cell surface thiol isomerases may explain the platelet-selective action of S-nitrosoglutathione

Xiao

Gordge

2011

Nitric Oxide

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“…S -nitrosoglutathione exhibits higher stability than • NO, mediates protein S -nitrosation and plays an important role in vascular signaling [ 9 ]. Therapeutic potential of GSNO has been shown through a systemic [ 10 ] vasorelaxant effect associated with a potent inhibitory effect of platelet functions [ 11 , 12 ]. Concerning its impact following stroke, several studies from Khan et al .…”

Section: Introductionmentioning

confidence: 99%

In Situ Microparticles Loaded with S-Nitrosoglutathione Protect from Stroke

et al. 2015

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Treatment of stroke, especially during the first hours or days, is still lacking. S-nitrosoglutathione (GSNO), a cerebroprotective agent with short life time, may help if administered early with a sustain delivery while avoiding intensive reduction in blood pressure. We developed in situ forming implants (biocompatible biodegradable copolymer) and microparticles (same polymer and solvent emulsified with an external oily phase) of GSNO to lengthen its effects and allow cerebroprotection after a single subcutaneous administration to Wistar rats. Arterial pressure was recorded for 3 days (telemetry, n = 14), whole-blood platelet aggregation up to 13 days (aggregometry, n = 58), and neurological score, cerebral infarct size and edema volume for 2 days after obstruction of the middle cerebral artery by autologous blood clots (n = 30). GSNO-loaded formulations (30 mg/kg) induced a slighter and longer hypotension (-10 vs. -56 ± 6 mmHg mean arterial pressure, 18 h vs. 40 min) than free GSNO at the same dose. The change in pulse pressure (-50%) lasted even up to 42 h for microparticles. GSNO-loaded formulations (30 mg/kg) prevented the transient 24 h hyper-aggregability observed with free GSNO and 7.5 mg/kg-loaded formulations. When injected 2 h after stroke, GSNO-loaded microparticles (30 mg/kg) reduced neurological score at 24 (-62%) and 48 h (-75%) vs. empty microparticles and free GSNO 7.5 mg/kg and, compared to free GSNO, divided infarct size by 10 and edema volume by 8 at 48 h. Corresponding implants reduced infarct size and edema volume by 2.5 to 3 times. The longer (at least 2 days) but slight effects on arterial pressures show sustained delivery of GSNO-loaded formulations (30 mg/kg), which prevent transient platelet hyper-responsiveness and afford cerebroprotection against the consequences of stroke. In conclusion, in situ GSNO-loaded formulations are promising candidates for the treatment of stroke.

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“…The delivery of an NO-related signal into cells by a stable S-nitrosothiol compound was demonstrated to result in the denitrification of cell surface enzymes, in addition, to the transportation of intact S-nitroso-cysteine by the amino acid transport system (L-AT). The different roles of these pathways in platelets and vascular cells may partially explain the selective effects on platelets (16). …”

Section: Discussionmentioning

confidence: 99%

Inhibitory role of S-nitrosoglutathione in the aggregation of frozen platelets, and its effect on the expression of membrane glycoproteins

Zhang

Wang

et al. 2013

Experimental and Therapeutic Medicine

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The aim of this study was to explore the effects of S-nitrosoglutathione (GSNO) on the aggregation of frozen platelets, the platelet nitric oxide (NO) content and the expression of membrane glycoproteins. The level of frozen platelet aggregation was measured using a platelet aggregation analyzer, while the content of NO was measured by the nitrate reductase method and the expression of frozen platelet membrane glycoproteins was determined by flow cytometry. The level of frozen platelet aggregation was reduced from 35.47±2.93 to 24.43±3.07% following treatment with GSNO. The mean NO concentration in the 32 samples of frozen platelets treated with GSNO was 45.64±6.31 μmol/l, which was significantly higher compared with the concentration in the fresh liquid platelet group. There were no significant differences in the levels of PAC-1 in the fresh liquid platelet, frozen platelet and GSNO-treated frozen platelet groups; by contrast, significant differences were observed in the CD42b and CD62P levels. The platelet membrane glycoprotein expression levels in the frozen platelet and the GSNO-treated frozen platelet groups were not significantly different. The results of the study indicate that GSNO has potential as a cryoprotectant, due to its ability to increase the NO concentration in frozen platelets, inhibit platelet aggregation and maintain platelet function. It is likely that the molecular arrangement and structure of the frozen platelets were altered following GSNO treatment, or that the frozen platelets were affected by alternative mechanisms.

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S‐nitrosothiols as selective antithrombotic agents – possible mechanisms

Cited by 19 publications

References 108 publications

Cell surface thiol isomerases may explain the platelet-selective action of S-nitrosoglutathione

Cell surface thiol isomerases may explain the platelet-selective action of S-nitrosoglutathione

In Situ Microparticles Loaded with S-Nitrosoglutathione Protect from Stroke

Inhibitory role of S-nitrosoglutathione in the aggregation of frozen platelets, and its effect on the expression of membrane glycoproteins

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