Imperial College London
Portrait Picture

Emeritus Professor David Lane

Faculty of Medicine, Department of Immunology and Inflammation

Emeritus Professor of Haematology
 
 
 
//

Contact

 

+44 (0)20 3313 2295d.lane

 
 
//

Location

 

Commonwealth BuildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Andreou:2015:10.1371/journal.pone.0122410,
author = {Andreou, AP and Efthymiou, M and Yu, Y and Watts, HR and Noormohamed, FH and Ma, D and Lane, DA and Crawley, JTB},
doi = {10.1371/journal.pone.0122410},
journal = {PLOS One},
title = {Protective Effects of Non-Anticoagulant Activated Protein C Variant (D36A/L38D/A39V) in a Murine Model of Ischaemic Stroke},
url = {http://dx.doi.org/10.1371/journal.pone.0122410},
volume = {10},
year = {2015}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Ischaemic stroke is caused by occlusive thrombi in the cerebral vasculature. Although tissue-plasminogenactivator (tPA) can be administered as thrombolytic therapy, it has majorlimitations, which include disruption of the blood-brain barrier and an increased risk ofbleeding. Treatments that prevent or limit such deleterious effects could be of major clinicalimportance. Activated protein C (APC) is a natural anticoagulant that regulates thrombingeneration, but also confers endothelial cytoprotective effects and improved endothelialbarrier function mediated through its cell signalling properties. In murine models of stroke,although APC can limit the deleterious effects of tPA due to its cell signalling function, its anticoagulantactions can further elevate the risk of bleeding. Thus, APC variants such asAPC(5A), APC(Ca-ins) and APC(36-39) with reduced anticoagulant, but normal signallingfunction may have therapeutic benefit. Human and murine protein C (5A), (Ca-ins) and (36-39) variants were expressed and characterised. All protein C variants were secreted normally,but 5-20% of the protein C (Ca-ins) variants were secreted as disulphide-linked dimers.Thrombin generation assays suggested reductions in anticoagulant function of 50- to57-fold for APC(36-39), 22- to 27-fold for APC(Ca-ins) and 14- to 17-fold for APC(5A). Interestingly,whereas human wt APC, APC(36-39) and APC(Ca-ins) were inhibited similarly byprotein C inhibitor (t½ - 33 to 39 mins), APC(5A) was inactivated ~9-fold faster (t½ - 4 mins).Using the murine middle cerebral artery occlusion ischaemia/repurfusion injury model, incombination with tPA, APC(36-39), which cannot be enhanced by its cofactor protein S, significantlyimproved neurological scores, reduced cerebral infarct area by ~50% and reducedoedema ratio. APC(36-39) also significantly reduced bleeding in the brain induced by administrationof tPA, whereas wt APC did not. If our data can be extrapolated to clinical settings,then APC(36-39
AU  - Andreou,AP
AU  - Efthymiou,M
AU  - Yu,Y
AU  - Watts,HR
AU  - Noormohamed,FH
AU  - Ma,D
AU  - Lane,DA
AU  - Crawley,JTB
DO  - 10.1371/journal.pone.0122410
PY  - 2015///
SN  - 1932-6203
TI  - Protective Effects of Non-Anticoagulant Activated Protein C Variant (D36A/L38D/A39V) in a Murine Model of Ischaemic Stroke
T2  - PLOS One
UR  - http://dx.doi.org/10.1371/journal.pone.0122410
UR  - http://hdl.handle.net/10044/1/24526
VL  - 10
ER  -
Download