Cardiac Hemorrhage Precedes Hypertension-induced Fibrosis in Plasminogen Activator Inhibitor-1 Deficient Mice.

AIMS: Plasminogen activator inhibitor-1 (PAI-1) regulates plasmin-mediated proteolysis, thereby influencing vascular stability and tissue remodeling. Angiotensin II (AngII) induces an increase of PAI-1 during the development of ascending thoracic aortic aneurysm (ATAA). The purpose of this study was to determine whether deletion of PAI-1 influenced the development of ATAA.

METHODS AND

RESULTS

AngII was infused for 4 weeks in whole-body PAI-1 deficient (PAI-1-/-) mice and their wild-type littermates (PAI-1+/+) to examine the role of PAI-1 in ATAA. PAI-1 deficiency did not alter AngII-induced aortopathy but revealed a striking cardiac phenotype characterized by replacement fibrosis predominantly within the epicardium and posterior septum. Ferric iron, indicative of prior hemorrhage, was coincident with fibrosis. Similar phenotypes were observed in PAI-1-/- mice infused with norepinephrine for 4 weeks. To define the pathological events preceding cardiac fibrosis, either AngII or norepinephrine was infused for 1 week in PAI-1+/+ or -/- mice. Both infusions induced extensive epicardial hemorrhage and posterior septal fibrosis in PAI-1-/- mice. To explore the initiation of hemorrhage and fibrosis, mice were infused with AngII for approximately 1 day, resulting in diffuse hemorrhage and cardiomyocyte loss localized to the posterior septum of PAI-1-/- mice.

CONCLUSIONS

These findings support that, under hemodynamic stress, PAI-1 deficiency promotes early cardiac hemorrhage and cardiomyocyte loss, implicating plasmin-mediated proteolysis as an initiator of cardiac injury and fibrosis.