Cardiovascular Research Center, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
Am J Physiol Endocrinol Metab. 2013 Jul 15;305(2):E243-53. doi: 10.1152/ajpendo.00044.2013. Epub 2013 May 21.
Because doxorubicin (DOX)-containing chemotherapy causes left ventricular (LV) dysfunction and remodeling that can progress to heart failure, strategies to alleviate DOX cardiotoxicity are necessary to improve health outcomes of patients surviving cancer. Although clinical evidence suggests that aerobic exercise training (ET) can prevent cardiotoxicity in patients undergoing DOX chemotherapy, the physiological mechanisms involved have not been extensively studied, nor is it known whether compounds [such as resveratrol (RESV)] have similar beneficial effects. With the use of a murine model of chronic DOX exposure, this study compared the efficacy of modest ET to RESV treatment on exercise performance, LV remodeling, and oxidative stress resistance. Mice were divided into four groups that received saline, DOX (8 mg/kg ip, one time per week), DOX + RESV (4 g/kg diet, ad libitum), and DOX + ET (45 min of treadmill exercise, 5 days/wk) for 8 wk. LV function and morphology were evaluated by in vivo echocardiography. DOX caused adverse LV remodeling that was partially attenuated by modest ET and completely prevented by RESV. These effects were paralleled by improvements in exercise performance. The cardioprotective properties of ET and RESV were associated with reduced levels of atrial natriuretic peptide and the lipid peroxidation by-product, 4-hydroxy-2-nonenal. In addition, ET and RESV increased the expression of cardiac sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a, superoxide dismutase, mitochondrial electron transport chain complexes, and mitofusin-1 and -2 in mice administered DOX. Compared with modest ET, RESV more effectively prevented DOX-induced LV remodeling and was associated with the reduction of DOX-induced oxidative stress. Our findings have important implications for protecting patients against DOX-associated cardiac injury.
由于多柔比星（DOX）含有的化疗会导致左心室（LV）功能障碍和重塑，从而导致心力衰竭，因此有必要采取策略来减轻 DOX 的心脏毒性，以改善癌症幸存患者的健康状况。尽管临床证据表明，有氧运动训练（ET）可以预防接受 DOX 化疗的患者发生心脏毒性，但涉及的生理机制尚未得到广泛研究，也不知道化合物[如白藜芦醇（RESV）]是否具有类似的有益作用。本研究使用慢性 DOX 暴露的小鼠模型，比较了适度 ET 与 RESV 治疗对运动表现、LV 重塑和抗氧化应激能力的疗效。将小鼠分为四组，分别接受生理盐水、DOX（8 mg/kg ip，每周一次）、DOX+RESV（4 g/kg 饮食，随意摄取）和 DOX+ET（45 分钟跑步机运动，每周 5 天）治疗 8 周。通过体内超声心动图评估 LV 功能和形态。DOX 导致 LV 重塑，适度 ET 部分减轻，RESV 完全预防。这些效果与运动表现的改善相平行。ET 和 RESV 的心脏保护特性与心房利钠肽水平降低和脂质过氧化产物 4-羟基-2-壬烯醛减少有关。此外，ET 和 RESV 增加了 DOX 处理小鼠心肌肌浆网/内质网钙-ATP 酶 2a、超氧化物歧化酶、线粒体电子传递链复合物、线粒体融合蛋白-1 和-2 的表达。与适度 ET 相比，RESV 更有效地预防了 DOX 引起的 LV 重塑，并与 DOX 引起的氧化应激减少有关。我们的发现对保护患者免受 DOX 相关心脏损伤具有重要意义。
