Fan Rui, Wang Yao, Zhang Jinjin, An Xiangbo, Liu Shuang, Bai Jie, Li Jiatian, Lin Qiuyue, Xie Yunpeng, Liao Jiawei, Xia Yunlong
Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Department of Interventional Therapy, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Pharmaceuticals (Basel). 2023 Aug 28;16(9):1212. doi: 10.3390/ph16091212.
Doxorubicin, a widely used chemotherapeutic drug in clinical oncology, causes a series of cardiac side effects referred to as doxorubicin-induced cardiotoxicity. Hyperhomocysteinaemia is an independent risk factor for multiple cardiovascular diseases. However, whether hyperhomocysteinaemia contributes to doxorubicin-induced cardiotoxicity is currently unknown. In this study, we explored the pathogenic effects of hyperhomocysteinaemia induced by dietary methionine supplementation (2% wt/wt in rodent chow) in a mouse model of doxorubicin-induced cardiotoxicity. Our data showed that methionine supplementation doubled serum homocysteine levels, inducing mild hyperhomocysteinaemia. Doxorubicin at a cumulative dosage of 25 mg/kg body weight led to significant weight loss and severe cardiac dysfunction, which were further exacerbated by methionine-induced mild hyperhomocysteinaemia. Doxorubicin-induced cardiac atrophy, cytoplasmic vacuolisation, myofibrillar disarray and loss, as well as cardiac fibrosis, were also exacerbated by methionine-induced mild hyperhomocysteinaemia. Additional folic acid supplementation (0.006% wt/wt) prevented methionine-induced hyperhomocysteinaemia and inhibited hyperhomocysteinaemia-aggravated cardiac dysfunction and cardiomyopathy. In particular, hyperhomocysteinaemia increased both serum and cardiac oxidative stress, which could all be inhibited by folic acid supplementation. Therefore, we demonstrated for the first time that hyperhomocysteinaemia could exacerbate doxorubicin-induced cardiotoxicity in mice, and the pathogenic effects of hyperhomocysteinaemia might at least partially correlate with increased oxidative stress and could be prevented by folic acid supplementation. Our study provides preliminary experimental evidence for the assessment of hyperhomocysteinaemia as a potential risk factor for chemotherapy-induced cardiotoxicity in cancer patients.
阿霉素是临床肿瘤学中广泛使用的化疗药物，会引发一系列心脏副作用，即阿霉素诱导的心脏毒性。高同型半胱氨酸血症是多种心血管疾病的独立危险因素。然而，高同型半胱氨酸血症是否会导致阿霉素诱导的心脏毒性目前尚不清楚。在本研究中，我们在阿霉素诱导的心脏毒性小鼠模型中，探究了通过在啮齿动物饲料中补充蛋氨酸（2%重量/重量）诱导的高同型半胱氨酸血症的致病作用。我们的数据表明，补充蛋氨酸使血清同型半胱氨酸水平加倍，诱发了轻度高同型半胱氨酸血症。累积剂量为25mg/kg体重的阿霉素导致显著体重减轻和严重心脏功能障碍，而蛋氨酸诱导的轻度高同型半胱氨酸血症使其进一步恶化。阿霉素诱导的心脏萎缩、细胞质空泡化、肌原纤维紊乱和丢失以及心脏纤维化，也因蛋氨酸诱导的轻度高同型半胱氨酸血症而加剧。额外补充叶酸（0.006%重量/重量）可预防蛋氨酸诱导的高同型半胱氨酸血症，并抑制高同型半胱氨酸血症加重的心脏功能障碍和心肌病。特别是，高同型半胱氨酸血症增加了血清和心脏的氧化应激，而补充叶酸均可抑制这种氧化应激。因此，我们首次证明高同型半胱氨酸血症可加重小鼠阿霉素诱导的心脏毒性，高同型半胱氨酸血症的致病作用可能至少部分与氧化应激增加相关，且可通过补充叶酸来预防。我们的研究为评估高同型半胱氨酸血症作为癌症患者化疗诱导心脏毒性的潜在危险因素提供了初步实验证据。
