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DC Field | Value | Language |
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dc.contributor.author | Senchenkova, EY | - |
dc.contributor.author | Ansari, J | - |
dc.contributor.author | Becker, F | - |
dc.contributor.author | Vital, SA | - |
dc.contributor.author | Al-Yafeai, Z | - |
dc.contributor.author | Sparkenbaugh, EM | - |
dc.contributor.author | Pawlinski, R | - |
dc.contributor.author | Stokes, KY | - |
dc.contributor.author | Carroll, JL | - |
dc.contributor.author | Dragoi, AM | - |
dc.contributor.author | Qin, CX | - |
dc.contributor.author | Ritchie, RH | - |
dc.contributor.author | Sun, H | - |
dc.contributor.author | Cuellar-Saenz, HH | - |
dc.contributor.author | Rubinstein, MR | - |
dc.contributor.author | Han, YW | - |
dc.contributor.author | Orr, AW | - |
dc.contributor.author | Perretti, M | - |
dc.contributor.author | Granger, DN | - |
dc.contributor.author | Gavins, FNE | - |
dc.date.accessioned | 2019-09-05T13:01:49Z | - |
dc.date.available | 2019-07-23 | - |
dc.date.available | 2019-09-05T13:01:49Z | - |
dc.date.issued | 2019-07-03 | - |
dc.identifier.citation | Senchenkova EY, Ansari J, Becker F, Vital SA, Al-Yafeai Z, Sparkenbaugh EM, Pawlinski R, Stokes KY, Carroll JL, Dragoi AM, Qin CX. Novel role for the AnxA1-Fpr2/ALX signaling axis as a key regulator of platelet function to promote resolution of inflammation. Circulation. 2019 Jul 23;140(4):319-35. | en_US |
dc.identifier.issn | 1524-4539 | - |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/19067 | - |
dc.description.abstract | BACKGROUND: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role. METHODS: Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1-/-) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye-induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro. RESULTS: Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1-/- mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B2 and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 [Rap1] expression) to decrease αIIbβ3 activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5-13 mice/group or 7-10 humans/group.) Conclusions: AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (αIIbβ3) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology. | en_US |
dc.format.extent | 319 - 335 | - |
dc.language.iso | en | en_US |
dc.publisher | American Heart Association | en_US |
dc.subject | Annexin A1 | en_US |
dc.subject | Formyl peptide receptor | en_US |
dc.subject | Inflammation | en_US |
dc.subject | Integrins | en_US |
dc.subject | Stroke | en_US |
dc.subject | Thrombosis | en_US |
dc.title | Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation | en_US |
dc.type | Article | en_US |
dc.contributor.sponsor | This work was supported by National Institutes of Health grants HL134959- 01A1 (to Dr Gavins); HL098435, HL133497, HL141155, and GM121307 (to Dr Orr); GM121307 (to Dr Stokes); R01 HL142604-01 (to Dr Pawlinski); and RO1CA192111 (to Dr Han). This work is also supported by American Heart Association grant 19PRE34380751 (to Dr Al-Yafeai) and Wellcome Trust grant 086867/Z/08/Z (to Dr Perretti). | - |
dc.identifier.doi | https://doi.org/10.1161/CIRCULATIONAHA.118.039345 | - |
dc.relation.isPartOf | Circulation | - |
pubs.issue | 4 | - |
pubs.publication-status | Published | - |
pubs.volume | 140 | - |
dc.identifier.eissn | 1524-4539 | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
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