| First Author | Yeung J | Year | 2014 |
| Journal | Blood | Volume | 124 |
| Issue | 14 | Pages | 2271-9 |
| PubMed ID | 25100742 | Mgi Jnum | J:218330 |
| Mgi Id | MGI:5617307 | Doi | 10.1182/blood-2014-05-575878 |
| Citation | Yeung J, et al. (2014) Platelet 12-LOX is essential for FcgammaRIIa-mediated platelet activation. Blood 124(14):2271-9 |
| abstractText | Platelets are essential in maintaining hemostasis following inflammation or injury to the vasculature. Dysregulated platelet activity often results in thrombotic complications leading to myocardial infarction and stroke. Activation of the FcgammaRIIa receptor leads to immune-mediated thrombosis, which is often life threatening in patients undergoing heparin-induced thrombocytopenia or sepsis. Inhibiting FcgammaRIIa-mediated activation in platelets has been shown to limit thrombosis and is the principal target for prevention of immune-mediated platelet activation. In this study, we show for the first time that platelet 12(S)-lipoxygenase (12-LOX), a highly expressed oxylipin-producing enzyme in the human platelet, is an essential component of FcgammaRIIa-mediated thrombosis. Pharmacologic inhibition of 12-LOX in human platelets resulted in significant attenuation of FcgammaRIIa-mediated aggregation. Platelet 12-LOX was shown to be essential for FcgammaRIIa-induced phospholipase Cgamma2 activity leading to activation of calcium mobilization, Rap1 and protein kinase C activation, and subsequent activation of the integrin alphaIIbbeta3. Additionally, platelets from transgenic mice expressing human FcgammaRIIa but deficient in platelet 12-LOX, failed to form normal platelet aggregates and exhibited deficiencies in Rap1 and alphaIIbbeta3 activation. These results support an essential role for 12-LOX in regulating FcgammaRIIa-mediated platelet function and identifies 12-LOX as a potential therapeutic target to limit immune-mediated thrombosis. |
