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

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Abstract
Aims: Plasminogen activator inhibitor-1 (PAI-1) regulates plasmin-mediated proteolysis, thereby influencing vascular stability and tissue remodeling. Angiotensin II (AngII) induces an increase in PAI-1 during the development of ascending thoracic aortic aneurysm (ATAA). The initial purpose of this study was to determine whether deletion of PAI-1 influenced development of ATAA. Subsequently, this study aimed to define the early pathological events preceding cardiac fibrosis in PAI-1 deficiency and the structural domain responsible for its protective effect. 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 cardiac pathology, AngII was infused for approximately 1 day. PAI-1−/− mice developed diffuse hemorrhage and cardiomyocyte injury localized to the posterior septum, pathologic changes that preceded overt fibrosis. Finally, to determine the protective domain of PAI-1, saline or AngII was administered to mice harboring loss-of-function point mutations in the protease inhibitory (PAI-1 Ala/Ala ) or somatomedin B-binding domains (PAI-1 AK/AK ). Compared to saline infusion, 1 week of AngII induced hemorrhage and heterogeneous fibrosis in PAI-1 Ala/Ala , but not PAI-1 AK/AK mice. Conclusions: These findings support that, under hemodynamic stress, PAI-1 deficiency promotes early cardiac hemorrhage and cardiomyocyte injury that lead to fibrosis. Mutational studies implicate dysregulated plasmin generation 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. Mutational disruption of the protease-inhibitory domain of PAI-1 induced similar pathology, supporting a protective role for this function. These observations suggest that interventions aimed at controlling hypertension, promoting endothelial integrity, or regulating plasmin activation could reduce fibrotic remodeling in this population.
Funding Information
  • National Institutes of Health (R35HL155649)
  • National Institutes of Health (TL1TR001997)
  • National Institutes of Health (R01HL078871)
  • National Institutes of Health (R01HL163870)
  • American Heart Association (23MERIT1036341)

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