Protective effects of phosphocreatine against Doxorubicin-Induced cardiotoxicity through mitochondrial function enhancement and apoptosis suppression via AMPK/PGC-1α signaling pathway

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2024-11-23 DOI:10.1016/j.intimp.2024.113677

Eskandar Qaed , Marwan almoiliqy , Wu Liu , Haitham Saad Al-mashriqi , Eman Alyafeai , Waleed Aldahmash , Mueataz A. Mahyoub , Zeyao Tang

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Abstract

Doxorubicin (DOX), a potent chemotherapy drug, is limited by its cardiotoxic effects, which can lead to heart damage. This study explores the cardioprotective potential of Phosphocreatine (PCr) in vitro and in vivo models, focusing on its impact on the AMPK and PGC-1α pathways, apoptosis reduction, and mitochondrial function preservation. Advanced methodologies, including high-resolution respirometry (HRR), were employed to assess mitochondrial bioenergetics, AMPK activity, and apoptotic rates in cardiomyocytes. Electrocardiography (ECG) and echocardiography (echo) were used to monitor cardiac function in vivo. Results showed that PCr significantly activated the AMPK and PGC-1α pathways, reduced apoptosis, and stabilized mitochondrial function in cardiomyocytes exposed to DOX. There was an upregulation of AMPK and PGC-1α target genes, stabilization of mitochondrial membranes, and improvements in cellular energy production and antioxidant defenses. PCr also markedly reduced apoptotic markers, enhancing cardiomyocyte viability. ECG and echocardiography revealed that PCr preserved cardiac function, indicated by improved heart rate variability, reduced QT interval prolongation, and enhanced ejection fraction. These findings highlight PCr’s potential in mitigating DOX-induced cardiotoxicity by enhancing mitochondrial function and reducing apoptosis. The study underscores the promise of PCr as an agent to reduce chemotherapy-related cardiac injuries, paving the way for further research to improve patient outcomes in cancer treatment.

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通过 AMPK/PGC-1α 信号通路增强线粒体功能和抑制细胞凋亡，磷酸肌酸对多柔比星诱导的心脏毒性具有保护作用

多柔比星（Doxorubicin，DOX）是一种强效化疗药物，但由于其心脏毒性作用而受到限制，可导致心脏损伤。本研究探讨了磷肌酸（PCr）在体外和体内模型中的心脏保护潜力，重点关注其对 AMPK 和 PGC-1α 通路、减少细胞凋亡和线粒体功能保护的影响。我们采用了包括高分辨率呼吸测定法（HRR）在内的先进方法来评估线粒体生物能、AMPK 活性和心肌细胞的凋亡率。心电图（ECG）和超声心动图（echo）用于监测体内心脏功能。结果表明，PCr 能明显激活 AMPK 和 PGC-1α 通路，减少细胞凋亡，并稳定暴露于 DOX 的心肌细胞的线粒体功能。AMPK和PGC-1α靶基因上调，线粒体膜稳定，细胞能量生成和抗氧化防御能力提高。PCr 还能显著减少凋亡标志物，增强心肌细胞的活力。心电图和超声心动图显示，PCr 可保护心脏功能，表现为改善心率变异性、减少 QT 间期延长和提高射血分数。这些发现凸显了 PCr 通过增强线粒体功能和减少细胞凋亡来减轻 DOX 诱导的心脏毒性的潜力。这项研究强调了 PCr 作为一种药物减少化疗相关心脏损伤的前景，为进一步研究改善癌症治疗中患者的预后铺平了道路。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.