Laboratory of Membrane Transport, Department of Pharmacology and Psychobiology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
Laboratory of Cell Ultrastructure and Tissue Biology, Department of Histology and Embryology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
Pharmacol Rep. 2019 Aug;71(4):583-590. doi: 10.1016/j.pharep.2019.02.013. Epub 2019 Feb 20.
Doxorubicin (DOX)-related cardiotoxicity may expose cancer survivors to increased risk of cardiovascular morbidity and mortality. Here, we characterized the time course of DOX-induced cardiomyopathy in rats.
Sprague-Dawley male rats (12 wk old) received doxorubicin hydrochloride (1 mg/kg/d, ip) during 10 consecutive days and they were euthanized one (DOX1), two (DOX2) or four (DOX4) weeks after the last drug injection. Control group received NaCl 0.9% (ip). Hearts were mounted on a Langendorff perfusion system, left ventricle fragments were processed for microscopy and oxidative stress-related assays, and blood was collected for cardiac troponin I assay.
All DOX-treated groups showed swollen and vacuolated cardiomyocytes with myofilaments disarray and mitochondrial damage. These changes were already evident after one week and became more pronounced after four weeks. Cardiac troponin I plasma levels were significantly increased in DOX1 and further increased in DOX4 compared to control group. Increased oxidative damage to lipids was observed in DOX1, and to proteins in DOX4. Glutathione peroxidase activity increased in DOX4. The morphological changes resulted in cardiac remodeling, including interstitial fibrosis, apoptosis and significant impairment of both contractile and relaxation function in DOX 4 compared to control group. Hearts from all animals displayed an early reduction in the responsiveness to norepinephrine.
These findings support the view that DOX cardiotoxicity occurs in a "continuum", and as the hypothesis of an irreversible cardiac injury is being challenged, understanding the progression of morphological and functional changes caused by DOX may allow proper timing of initiation of prophylactic treatment.
多柔比星（DOX）相关的心脏毒性可能会使癌症幸存者面临更高的心血管发病率和死亡率风险。在这里，我们描述了 DOX 诱导的大鼠心肌病的时程变化。
12 周龄雄性 Sprague-Dawley 大鼠（n=10）在 10 天内连续接受盐酸多柔比星（1mg/kg/d，腹腔注射），最后一次给药后 1（DOX1）、2（DOX2）或 4 周（DOX4）处死。对照组接受生理盐水（腹腔注射）。心脏置于 Langendorff 灌流系统上，左心室片段用于显微镜检查和氧化应激相关测定，血液用于心肌肌钙蛋白 I 测定。
所有 DOX 处理组均显示出心肌细胞肿胀和空泡化，肌原纤维排列紊乱和线粒体损伤。这些变化在一周后就已经很明显，四周后更为明显。与对照组相比，DOX1 和 DOX4 组的心肌肌钙蛋白 I 血浆水平显著升高。在 DOX1 中观察到脂质氧化损伤增加，在 DOX4 中观察到蛋白质氧化损伤增加。DOX4 组谷胱甘肽过氧化物酶活性增加。形态学变化导致心脏重构，包括间质纤维化、凋亡以及与对照组相比，DOX4 组的收缩和舒张功能显著受损。所有动物的心脏对去甲肾上腺素的反应性均较早降低。
这些发现支持 DOX 心脏毒性呈“连续”发生的观点，随着不可逆性心肌损伤假说受到挑战，了解 DOX 引起的形态和功能变化的进展可能有助于适当选择预防性治疗的时机。
