Abstract 16826: Deletion of the Von Willebrand Factor Receptor, GpIbα, Reduces Myocardial Infarction Size while Increasing Atherosclerosis and Inflammation
Platelet GpIbα mediates platelet adhesion by binding to Von Willebrand Factor (vWF). Rupture of atherosclerosis followed by thrombosis is the underlying mechanism of acute coronary syndrome. Inflammation renders plaques unstable linking inflammation and thrombosis in atherogenesis. In vitro evidence suggests a direct interaction between the leukocyte Mac-1 and GpIbα. However, in vivo studies are incomplete and represent a major gap in our understanding of the inflammation/thrombosis axis. Furthermore, the role of GpIbα in myocardial infarction (MI) models has never been investigated. We hypothesized that GpIbα modulates atherosclerosis and worsens infarct size by mediating not only thrombus formation but also inflammation via platelet interaction with monocyte.
Methods: We study in vivo interactions between inflammation and thrombosis using mouse models expressing dysfunctional variants of the GpIbα, i.e. GpIbα−/− mice and mice reconstituted with chimeric IL4 receptor extracellular domain and GpIbα cytoplasmic domain (IL4R) to avoid thrombocytopenia seen in the GpIbα knock-out. These animals are crossed with LDLr deleted mice then fed on high fat diet. Atherosclerotic lesions are analyzed for macrophage accumulation and plaque morphology by immunohistochemistry. Thioglycollate peritonitis model was used to assess leukocyte migration in vivo. Platelet-monocyte interaction is analyzed using flow cytometry. Furthermore, ischemia/reperfusion is induced in wild type, GpIbα−/− and IL4-R mice by ligation of left coronary artery. Infarct size is measured by triphenyltetrazolium chloride (TTC) staining.
Results: GpIbα deletion increases atherosclerosis in both GpIbα/LDLr double knock-out (DKO) and IL4R/LDLr DKO compared to LDLr−/−. An in vivo model of peritonitis shows GpIbα deletion increases leukocyte migration 4-fold and abrogates platelet-monocyte binding, suggesting platelet GpIbα inhibits inflammatory pathways. Importantly, GpIbα deletion causes reduction of infarct area.
Conclusions: GpIbα shows an atheroprotective effect by mediating interaction between monocyte and platelets. In contrast, in an ischemia-reperfusion/MI setting, by limiting thrombus formation, inhibition of GpIbα reduces myocardial damage.
- © 2010 by American Heart Association, Inc.