Plasminogen Activator Inhibitor‐1 Deficiency Exacerbates Pressure Overload‐Induced Cardiac Hypertrophy in Mice
5 affiliations
- 1The First Hospital of Jilin University
- 2The Affiliated Hospital of Southwest Medical University
- 3Yanbian University
- 4Nagoya University Graduate School of Medicine
- 5Yanbian University Hospital
Abstract
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: ) 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.
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BibTeX
@article{huang2026plasminogen,
title = {{Plasminogen Activator Inhibitor‐1 Deficiency Exacerbates Pressure Overload‐Induced Cardiac Hypertrophy in Mice}},
author = {Chaoqun Huang and Shangzhi Shu and Xueling Yue and Jinshun Piao and Megumi Narisawa and Chongning Zhong and Longguo Zhao and Na Wang and Huayang Zhang and Yongyan Chen and Meiping Zhang and Xian Wu Cheng and Shuyan Li},
journal = {Journal of the American Heart Association},
year = {2026},
month = oct,
doi = {10.1161/jaha.126.052213},
url = {https://www.ahajournals.org/doi/10.1161/JAHA.126.052213},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Plasminogen Activator Inhibitor‐1 Deficiency Exacerbates Pressure Overload‐Induced Cardiac Hypertrophy in Mice
AU - Chaoqun Huang
AU - Shangzhi Shu
AU - Xueling Yue
AU - Jinshun Piao
AU - Megumi Narisawa
AU - Chongning Zhong
AU - Longguo Zhao
AU - Na Wang
AU - Huayang Zhang
AU - Yongyan Chen
AU - Meiping Zhang
AU - Xian Wu Cheng
AU - Shuyan Li
PY - 2026
DA - 2026/10/23
JO - Journal of the American Heart Association
DO - 10.1161/jaha.126.052213
UR - https://www.ahajournals.org/doi/10.1161/JAHA.126.052213
AB - 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: ) 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.
SN - 2047-9980
ER -