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Exacerbation of glycoprotein VI-dependent platelet responses in a rhesus monkey model of type 1 diabetes

Arthur, JF; Shen, Y.; Chen, Y.; Qiao, J.; Ni, R.; Lu, Y.; Andrews, Robert K; Gardiner, Elizabeth; Cheng, J.

Description

Thrombosis is a life-threatening complication of diabetes. Platelet reactivity is crucial to thrombus formation, particularly in arterial vessels and in thrombotic complications causing myocardial infarction or ischaemic stroke, but diabetic patients often respond poorly to current antiplatelet medication. In this study, we used a nonhuman primate model of Type 1 diabetes to measure early downstream signalling events following engagement of the major platelet collagen receptor, glycoprotein...[Show more]

dc.contributor.authorArthur, JF
dc.contributor.authorShen, Y.
dc.contributor.authorChen, Y.
dc.contributor.authorQiao, J.
dc.contributor.authorNi, R.
dc.contributor.authorLu, Y.
dc.contributor.authorAndrews, Robert K
dc.contributor.authorGardiner, Elizabeth
dc.contributor.authorCheng, J.
dc.date.accessioned2018-11-29T22:57:23Z
dc.date.available2018-11-29T22:57:23Z
dc.identifier.issn2314-6745
dc.identifier.urihttp://hdl.handle.net/1885/153853
dc.description.abstractThrombosis is a life-threatening complication of diabetes. Platelet reactivity is crucial to thrombus formation, particularly in arterial vessels and in thrombotic complications causing myocardial infarction or ischaemic stroke, but diabetic patients often respond poorly to current antiplatelet medication. In this study, we used a nonhuman primate model of Type 1 diabetes to measure early downstream signalling events following engagement of the major platelet collagen receptor, glycoprotein (GP)VI. Diabetic monkeys were given enough insulin to maintain their blood glucose levels either at ~8 mM (well-controlled diabetes) or ~15 mM (poorly controlled diabetes). Flow cytometric analysis was used to measure platelet reactive oxygen species (ROS) generation, calcium mobilisation, receptor surface expression, and immature platelet fraction. We observed exacerbated intracellular ROS and calcium flux associated with engagement of GPVI in monkeys with poorly controlled diabetes. GPVI surface levels did not differ between healthy monkeys or the two diabetic groups. Treatment of platelets with the specific Syk inhibitor BAY61-3606 inhibited GPVI-dependent ROS and, importantly, reduced ROS generation in the poorly controlled diabetes group to that observed in healthy monkeys. These data indicate that glycaemic control is important in reducing GPVI-dependent platelet hyperreactivity and point to a potential antithrombotic therapeutic benefit of Syk inhibition in hyperglycaemic diabetes
dc.format.mimetypeapplication/pdf
dc.publisherHindawi Publishing Corporation
dc.sourceJournal of Diabetes Research
dc.subjectKeywords: bay 613606; glucose; glycoprotein VI; protein kinase Syk; protein kinase Syk inhibitor; reactive oxygen metabolite; unclassified drug; 2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; calcium; fibrinogen receptor; nicotinamide; pl
dc.titleExacerbation of glycoprotein VI-dependent platelet responses in a rhesus monkey model of type 1 diabetes
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume2013
dc.date.issued2013
local.identifier.absfor060110 - Receptors and Membrane Biology
local.identifier.ariespublicationU3488905xPUB17155
local.type.statusPublished Version
local.contributor.affiliationArthur, JF, Australian Centre for Blood Diseases, Monash University
local.contributor.affiliationShen, Y., Australian Centre for Blood Diseases, Monash University
local.contributor.affiliationChen, Y., Sichuan University
local.contributor.affiliationQiao, J., Australian Centre for Blood Diseases, Monash University
local.contributor.affiliationNi, R., Sichuan University
local.contributor.affiliationLu, Y., Sichuan University
local.contributor.affiliationAndrews, Robert K, Monash University
local.contributor.affiliationGardiner, Elizabeth, College of Health and Medicine, ANU
local.contributor.affiliationCheng, J., Sichuan University
local.bibliographicCitation.startpage370212
local.bibliographicCitation.lastpage370212
local.identifier.doi10.1155/2013/370212
dc.date.updated2018-11-29T08:17:39Z
local.identifier.scopusID2-s2.0-84879406310
local.identifier.thomsonID000320527400001
dcterms.accessRightsOpen Access
CollectionsANU Research Publications

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