Abstract Body: Background: Plasminogen Activator Inhibitor-1 (PAI-1) plays a crucial role in age-related cardiovascular diseases (CVD). We investigate the effects of PAI-1 reduction on cardiovascular physiology using genetically engineered mouse models.
Methods: The study utilized a novel mouse line with a dinucleotide duplication mutation in Serpine1exon 4. L-NAME treatment was used to model aging-related vascular stiffening on heterozygous mutated mice (Serpine1^TA700/+). Cardiovascular physiology was assessed through measurements of systolic blood pressure, diastolic function, and aortic pulse wave velocity. We used a mouse model overexpressing the stabilized human PAI-1 protein and assessed physiological changes with chronological age. Bulk and single-cell RNA sequencing of aortic tissue was performed to identify genetic candidates for protection against aging-like pathophysiology. Lastly, PAI-1 inhibitor TM5614 was used to test the reversal of L-NAME-induced pathophysiology.
Results: Serpine1^TA700/+ mice exhibited a 20% longer overall survival compared to controls. These mice also showed attenuated increases in SBP, E/e', and PWV following L-NAME treatment. Conversely, mice overexpressing stabilized human PAI-1 displayed exacerbated cardiovascular pathophysiology. Bulk and single-cell RNA sequencing revealed reduced expression of Ccn1, Npnt, and Itgb1 in Serpine1^TA700/+ mice, suggesting potential mechanisms for vascular protection. Pharmacological inhibition of PAI-1 with TM5614 reversed L-NAME-induced increases in PWV.
Conclusion: Genetic reduction of PAI-1 protects against aging-related cardiovascular pathophysiology, while PAI-1 overexpression exacerbates these effects. Pharmacological inhibition of PAI-1 reverses pre-existing aging-related cardiovascular pathology, highlighting its potential as a therapeutic strategy for combating cardiovascular aging and related pathologies.