Abstract Or144: Plasminogen Activator Inhibitor-1 Deficiency Induces Cardiac Hemorrhage and Augments Cardiac Fibrosis, but not Aortic Aneurysm, in Angiotensin II-infused Mice

Background: Plasminogen activator inhibitor-1 (PAI-1), the primary regulator of fibrinolysis, is highly abundant in human thoracic aortic aneurysms (TAA), and in the ascending aortas of mice infused with angiotensin II (AngII) prior to overt pathology. The purpose of this study was to determine whether deletion of PAI-1 influenced the development of TAAs during AngII infusion. Methods and Results: To determine the role of PAI-1 in AngII-induced pathology, whole-body PAI-1 deficient mice (PAI-1 -/-) and wild type littermates (PAI-1 +/+) were infused with AngII (1,000 ng/kg/min) for 28 days. Despite the upregulation of PAI-1 in TAA, aortic dimensions were not altered by PAI-1 deficiency, determined by ultrasonography and in situ measurement. However, PAI-1 deficiency augmented grossly visible and histologically evident cardiac fibrosis, primarily within the epicardium. Because of PAI-1’s role in regulating fibrinolysis, we next investigated whether cardiac hemorrhage preceded fibrosis in PAI-1 -/- mice. Profound accumulation of ferric iron, an indicator of erythrocyte degradation, was observed coincidently with cardiac fibrosis in PAI-1 -/- mice by Prussian blue staining. Ferric iron was minimally observed in PAI-1 +/+ mice. To verify the presence of cardiac hemorrhage, we infused PAI-1 +/+ and -/- mice with AngII for 1 and 7 days. Cardiac hemorrhage was observed by 1 day of infusion in PAI-1 -/- mice by in situ imaging, hematoxylin-eosin, and Ter119 staining. Furthermore, by 7 days of AngII, cardiac hemorrhage was increased in PAI-1 -/- mice compared to 1 day of infusion and was concentrated within the epicardium. To investigate whether PAI-1 deficiency induces cardiac dysfunction in relation to the observed pathology, PAI-1 +/+ and -/- mice were infused with saline or AngII and measured by echocardiography at baseline, 7, and 28 days of infusion. Measures of ejection fraction, global longitudinal strain, and global circumferential strain were minimally altered by PAI-1 deficiency. However, the posterior left ventricular wall diameter in diastole and calculated left ventricular mass of AngII-infused PAI-1 -/- mice were increased, suggesting the augmentation of AngII-induced cardiomegaly. Conclusion: PAI-1 deficiency does not affect TAA formation, but induces cardiac hemorrhage and augments cardiomegaly and fibrosis in AngII-infused mice.