膜联蛋白A1
医学
炎症
血小板活化
血小板
活体显微镜检查
药理学
病理
免疫学
内科学
膜联蛋白
微循环
染色
作者
Elena Y. Senchenkova,Junaid Ansari,Felix Becker,Shantel Vital,Zaki Al‐Yafeai,Erica Sparkenbaugh,Rafał Pawliński,Karen Y. Stokes,Jennifer L. Carroll,Ana Maria Dragoi,Cheng Xue Qin,Rebecca H. Ritchie,Hai Sun,Hugo Cuellar,Mara Roxana Rubinstein,Yiping W. Han,A. Wayne Orr,Mauro Perretti,D. Neil Granger,Felicity N. E. Gavins
出处
期刊:Circulation
[Ovid Technologies (Wolters Kluwer)]
日期:2019-07-23
卷期号:140 (4): 319-335
被引量:98
标识
DOI:10.1161/circulationaha.118.039345
摘要
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 B 2 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 α IIb β 3 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 (α IIb β 3 ) 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.
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