Abstract 2023: Plasminogen Activator Inhibitor-1 Deficiency Augments Angiotensin II-induced Cardiac Fibrosis, But Not Aortic Aneurysm Formation In Mice

Abstract

Background: Plasminogen activator inhibitor-1 (PAI-1) is highly abundant in human thoracic aortic aneurysms (TAA). This high abundance is mimicked in TAAs created by chronic infusion of angiotensin II (AngII) into mice. The purpose of this study was to determine whether deletion of PAI-1 influenced the development of thoracic aortic aneurysms during AngII infusion. Methods and Results: To determine the role of PAI-1 in acute and chronic phases of 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 7 or 28 days, respectively. Aortic diameters were measured by ultrasonography and in situ measurement. PAI-1 deficiency did not alter maximal luminal or external aortic diameters at 7 or 28 days of AngII. At 7 days of AngII, ventricular hemorrhage was visibly evident in PAI-1 -/- mice. Mid-ventricular heart sections were next examined by hematoxylin and eosin staining, and red blood cell accumulation was found primarily within the epicardium. Masson’s trichrome staining revealed interstitial fibrosis in the epicardium, myocardium, and posterior septum of PAI-1 -/- mice. At 28 days of AngII, PAI-1 -/- mice displayed primarily epicardial fibrosis evident by trichrome staining and gross appearance. The posterior septum presented less fibrosis after 28 days of AngII relative to 7 days of AngII. Conclusions: PAI-1 deficiency did not alter aortic dilatation, indicating that PAI-1 is not a key contributor to AngII-induced TAAs. Paradoxically, PAI-1 deficiency augmented AngII-induced cardiac fibrosis with distinct distributions between acute and chronic phases.