Relation of preexisting anti-β2GPI antibodies to infarct size in a rat model

Abstract

Background: Anti-β2-glycoprotein I (β2GPI) antibodies (a subpopulation of antiphospholipid (aPL) antibodies) are associated with a procoagulant state in humans and with enhanced atherosclerosis in experimental animal models. Moreover, the presence of high titers of aPL antibodies in relatively young patients is associated with higher incidence of subsequent myocardial infarction. Herein, we evaluated the role of preexisting high levels of aPL antibodies in determining the size of the infarct induced by permanent ligation of the left anterior descending artery (LAD) in a rat model. Methods and results: A total of 11 Wistar rats were immunized and boosted with 10 μg of the phospholipid binding protein —β2GPI (a method commonly applied for induction of aPL antibodies). Rats in the control group ( n=9) were immunized and boosted with a Freund's adjuvant. Upon development of high anti-β2GPI antibodies levels, myocardial infarction was induced by ligation of the LAD coronary artery. Rats were sacrificed 7 days later, their lymph nodes were collected for evaluation of cellular immunity to β2GPI and their hearts were removed for assessment of infarct size and for immunohistochemical stains for iNOS and TGF-beta. β2GPI-immunized rats exhibited high levels of aPL antibodies (mean optical density of 1.3±0.3) as compared with the control group (mean optical density of 0.12±0.03; P<.0001). Cellular immunity to β2GPI was also pronounced as evident by an increased thymidine uptake and by increased interferon gamma secretion by the lymph node cells from β2GPI-immunized rats. Myocardial infarct size has shown a tendency to be increased in rats induced to develop anti-β2GPI antibodies (mean size 23±9%) as compared with controls (17±12%; P<.23). iNOS positive cells in the infarct area of β2GPI-immunized rats were significantly increased in comparison to the control group ( P<.01). Similarly, TGF-beta cell expression was significantly increased in the infarct area of the immunized rats in comparison to the control group (22.6±5.1 and 7±2.1 per 100 mononuclear inflammatory cells, respectively; P=.01). Conclusion: The presence of high levels of aPL antibodies is associated with higher expression of iNOS and TGF-beta and may contribute to myocardial damage.