PP2Acα deficiency attenuates doxorubicin-induced cardiac injury by suppressing cardiomyocyte apoptosis
- 1Department of Cardiology, The Second Nanning People’s Hospital
- 2Department of Cardiology, The Affiliated Jiangning Hospital of Nanjing Medical University
Abstract
Background: Doxorubicin cardiotoxicity is a major clinical concern, but the role of PP2Ac α in this process remains unknown. This study investigated its involvement and underlying mechanisms.
Methods: A mouse model of doxorubicin-induced myocardial injury was established. Cardiac function, cardiac morphology, cardiomyocyte size, myocardial fibrosis, and apoptosis were assessed by echocardiography, H&E staining, Masson's trichrome staining, immunofluorescence, TUNEL staining, qRT-PCR, and Western blotting. Cardiac-specific Ppp2ca conditional knockout mice ( Ppp2ca cKO ) were used to evaluate the effect of Ppp2ca deletion on doxorubicin cardiotoxicity. In vitro , cultured cardiomyocytes were treated with varying concentrations of doxorubicin, and PP2Ac α expression was silenced using Ppp2ca -siRNA to assess cell viability and apoptosis-related protein expression.
Results: Doxorubicin treatment significantly reduced left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), accompanied by increased left ventricular internal diameter at systole, reduced wall thickness, decreased heart weight-to-tibia length ratio, and reduced cardiomyocyte cross-sectional area, indicating impaired systolic function and myocardial atrophy; Doxorubicin also upregulated Ppp2ca mRNA and PP2Ac α protein expression in myocardial tissues and cardiomyocytes, while decreasing the anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic proteins Bax and cleaved Caspase-3. Compared with Ppp2ca flox/flox mice, Ppp2ca cKO mice showed markedly attenuated cardiac dysfunction, cardiac atrophy, and cardiomyocyte size reduction after doxorubicin treatment. Masson's staining and Col1a1 /Col3a1 mRNA analysis further showed reduced myocardial collagen deposition. Moreover, the increase in TUNEL-positive cells and the abnormal expression of apoptosis-related proteins were markedly attenuated by Ppp2ca deletion. In vitro siRNA experiments confirmed that Ppp2ca knockdown improved cardiomyocyte viability and mitigated changes in apoptosis-related proteins after doxorubicin treatment.
Conclusion: Doxorubicin induces PP2Ac α upregulation in myocardial tissues and cardiomyocytes, whereas Ppp2ca deletion or knockdown effectively alleviates doxorubicin-induced cardiac dysfunction, myocardial fibrosis, and cardiomyocyte apoptosis. PP2Ac α acts as a key pro-injury factor in doxorubicin cardiotoxicity, and targeting Ppp2ca may represent a potential strategy for preventing anthracycline-induced cardiotoxicity.
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BibTeX
@article{huang2026pp2acα,
title = {{PP2Acα deficiency attenuates doxorubicin-induced cardiac injury by suppressing cardiomyocyte apoptosis}},
author = {Wei Huang and Xingyu Jiang and Wenjing Xu and Hao Zhang and Youpeng Geng and Lai Zhang and Chao Fang and Qin Tao},
journal = {Frontiers in Cardiovascular Medicine},
year = {2026},
month = nov,
doi = {10.3389/fcvm.2026.1994338},
url = {https://www.frontiersin.org/articles/10.3389/fcvm.2026.1994338/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PP2Acα deficiency attenuates doxorubicin-induced cardiac injury by suppressing cardiomyocyte apoptosis
AU - Wei Huang
AU - Xingyu Jiang
AU - Wenjing Xu
AU - Hao Zhang
AU - Youpeng Geng
AU - Lai Zhang
AU - Chao Fang
AU - Qin Tao
PY - 2026
DA - 2026/11/04
JO - Frontiers in Cardiovascular Medicine
DO - 10.3389/fcvm.2026.1994338
UR - https://www.frontiersin.org/articles/10.3389/fcvm.2026.1994338/full
AB - Background: Doxorubicin cardiotoxicity is a major clinical concern, but the role of PP2Ac α in this process remains unknown. This study investigated its involvement and underlying mechanisms. Methods: A mouse model of doxorubicin-induced myocardial injury was established. Cardiac function, cardiac morphology, cardiomyocyte size, myocardial fibrosis, and apoptosis were assessed by echocardiography, H&E staining, Masson's trichrome staining, immunofluorescence, TUNEL staining, qRT-PCR, and Western blotting. Cardiac-specific Ppp2ca conditional knockout mice ( Ppp2ca cKO ) were used to evaluate the effect of Ppp2ca deletion on doxorubicin cardiotoxicity. In vitro , cultured cardiomyocytes were treated with varying concentrations of doxorubicin, and PP2Ac α expression was silenced using Ppp2ca -siRNA to assess cell viability and apoptosis-related protein expression. Results: Doxorubicin treatment significantly reduced left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), accompanied by increased left ventricular internal diameter at systole, reduced wall thickness, decreased heart weight-to-tibia length ratio, and reduced cardiomyocyte cross-sectional area, indicating impaired systolic function and myocardial atrophy; Doxorubicin also upregulated Ppp2ca mRNA and PP2Ac α protein expression in myocardial tissues and cardiomyocytes, while decreasing the anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic proteins Bax and cleaved Caspase-3. Compared with Ppp2ca flox/flox mice, Ppp2ca cKO mice showed markedly attenuated cardiac dysfunction, cardiac atrophy, and cardiomyocyte size reduction after doxorubicin treatment. Masson's staining and Col1a1 /Col3a1 mRNA analysis further showed reduced myocardial collagen deposition. Moreover, the increase in TUNEL-positive cells and the abnormal expression of apoptosis-related proteins were markedly attenuated by Ppp2ca deletion. In vitro siRNA experiments confirmed that Ppp2ca knockdown improved cardiomyocyte viability and mitigated changes in apoptosis-related proteins after doxorubicin treatment. Conclusion: Doxorubicin induces PP2Ac α upregulation in myocardial tissues and cardiomyocytes, whereas Ppp2ca deletion or knockdown effectively alleviates doxorubicin-induced cardiac dysfunction, myocardial fibrosis, and cardiomyocyte apoptosis. PP2Ac α acts as a key pro-injury factor in doxorubicin cardiotoxicity, and targeting Ppp2ca may represent a potential strategy for preventing anthracycline-induced cardiotoxicity.
SN - 2297-055X
ER -