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Background: Doxorubicin (DOX), a widely used chemotherapeutic agent, causes severe cardiotoxicity that frequently progresses to dilated cardiomyopathy (DCM). While ankyrin repeat domain 1 protein (ANKRD1) plays critical roles in cardiovascular pathophysiology, its specific involvement in doxorubicin-induced DCM remains unknown. This study investigates the functional significance of ANKRD1 in DOX-induced DCM pathogenesis.
Results: DOX treatment significantly upregulated ANKRD1 expression in both rat models and H9c2 rat cardiomyocytes. In vivo, ANKRD1 knockdown ameliorated DOX-induced cardiac dysfunction, as demonstrated by improved left ventricular ejection fraction and fractional shortening, along with reduced serum levels of lactate dehydrogenase and creatine kinase-myocardial band. Conversely, ANKRD1 overexpression exacerbated cardiac impairment. Pathological examination revealed that ANKRD1 knockdown attenuated DOX-induced myocardial tissue damage and collagen deposition, while ANKRD1 overexpression intensified these pathological changes. Furthermore, ANKRD1 knockdown mitigated mitochondrial dysfunction and oxidative stress in DCM models both in vivo and in vitro. Mechanistically, ANKRD1 knockdown activated the AMP-activated protein kinase (AMPK)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling cascade, thereby attenuating DOX-induced cardiomyocyte toxicity, mitochondrial dysfunction, and oxidative stress. Rescue experiments using the AMPK inhibitor dorsomorphin confirmed this pathway’s involvement, as dorsomorphin treatment abolished the protective effects of ANKRD1 knockdown against DOX-induced cardiomyocyte damage.
Conclusions: ANKRD1 knockdown prevents DOX-induced DCM by ameliorating mitochondrial dysfunction and oxidative stress through activation of the AMPK/AKT/mTOR pathway. These findings establish ANKRD1 as a promising therapeutic target for preventing DOX-induced cardiotoxicity and DCM.
References
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