Cardiac Hemorrhage Precedes Hypertension-induced Fibrosis in Plasminogen Activator Inhibitor-1 Deficient Mice
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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.
TRANSLATIONAL PERSPECTIVE
Cardiac fibrosis has been reported in a human population with PAI-1 deficiency and currently lacks targeted therapy. Our findings demonstrate that in animal models, PAI-1 deficiency confers susceptibility to cardiac injury in response to hemodynamic stress, which may accelerate fibrotic remodeling. These observations suggest that interventions aimed at controlling hypertension, promoting endothelial integrity, or regulating plasmin activation could reduce fibrotic remodeling in this population.
