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

Background 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. Methods 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. Results 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. Conclusions 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.