PP2Acα deficiency attenuates doxorubicin-induced cardiac injury by suppressing cardiomyocyte apoptosis

Abstrakts

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.