Plasminogen Activator Inhibitor-1 Deficiency Exacerbates Pressure Overload-Induced Cardiac Hypertrophy in Mice

Pathological cardiac hypertrophy is a key precursor to heart failure. PAI-1 (plasminogen activator inhibitor-1) is a recognized profibrotic mediator, yet its role in the heart remains paradoxical and incompletely understood.

Six-week-old male wild-type (PAI-1^+/+) and PAI-1 knockout (PAI-1^-/-) mice underwent sham or transverse aortic constriction surgery, followed by assessment of cardiac morphology, molecular markers, and function. In H9C2 cardiomyocytes, PAI-1 was silenced or overexpressed before angiotensin II stimulation, with or without targeted signaling inhibitors, followed by coimmunoprecipitation, Western blotting, and immunofluorescence.

Pressure overload increased plasma and myocardial PAI-1 levels. PAI-1 deficiency exacerbated transverse aortic constriction-induced cardiac dysfunction, hypertrophy, and fibrosis, accompanied by JAK2/STAT3 (Janus kinase 2/signal transducer and activator of transcription 3) activation and collagen overexpression, whereas cardiac-specific overexpression attenuated these maladaptive changes. Moreover, STAT3 inhibition reversed the adverse cardiac remodeling associated with PAI-1 deletion. In vitro, PAI-1 knockdown potentiated angiotensin II-induced cardiomyocyte hypertrophy, an effect that was rescued by PAI-1 overexpression. Mechanistically, PAI-1 associated with JAK2 and STAT3, with reduced phosphorylation of both proteins and impaired STAT3 nuclear translocation. Critically, pharmacological inhibition of STAT3 abolished the harmful effects of PAI-1 silencing.

PAI-1 acts as an endogenous cardioprotective checkpoint by negatively regulating JAK2/STAT3 signaling. These findings suggest a noncanonical cardiomyocyte-associated function of PAI-1 beyond its classical fibrinolytic role and identify the PAI-1-JAK2/STAT3 axis as a potential therapeutic target for heart failure with hypertrophy.