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Cardiac Hemorrhage Precedes Hypertension-induced Fibrosis in Plasminogen Activator Inhibitor-1 Deficient Mice
Alex C Pettey1,2, Sohei Ito2, Michael K Franklin2
1Department of Physiology, University of Kentucky, Lexington, KY.
Insights
Plasminogen activator inhibitor-1 (PAI-1) deficiency in mice led to cardiac hemorrhage and cardiomyocyte loss under stress, suggesting plasmin-mediated proteolysis initiates cardiac injury and fibrosis.
Area of Science:
- Cardiovascular Biology
- Proteolysis and Hemostasis
- Pathology
Background:
- Plasminogen activator inhibitor-1 (PAI-1) is crucial for regulating plasmin-mediated proteolysis, impacting vascular stability and tissue remodeling.
- Angiotensin II (AngII) elevates PAI-1 during ascending thoracic aortic aneurysm (ATAA) development.
Purpose of the Study:
- To investigate the role of PAI-1 in the development of ATAA by examining its absence.
- To determine if PAI-1 deficiency influences AngII-induced cardiovascular changes.
Main Methods:
- Infusion of AngII or norepinephrine in PAI-1 deficient (PAI-1-/-) and wild-type (PAI-1+/+) mice for varying durations (1 day to 4 weeks).
- Assessment of aortopathy, cardiac fibrosis, hemorrhage, and cardiomyocyte loss.
Main Results:
- PAI-1 deficiency did not affect AngII-induced aortopathy but caused significant cardiac fibrosis, particularly epicardial and septal.
- Hemorrhage, indicated by ferric iron, coincided with fibrosis in PAI-1-/- mice.
- Early AngII or norepinephrine infusion in PAI-1-/- mice induced epicardial hemorrhage and posterior septal fibrosis, with hemorrhage and cardiomyocyte loss observed after 1 day.
Conclusions:
- PAI-1 deficiency promotes early cardiac hemorrhage and cardiomyocyte loss under hemodynamic stress.
- Plasmin-mediated proteolysis is implicated as an initiator of cardiac injury and subsequent fibrosis.
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.
