Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice
Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice
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DOI：
10.1152/ajpendo.00044.2013
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发表时间：
2013-07-01
影响因子：
5.1
通讯作者：
Dyck, Jason R. B.
中科院分区：
文献类型：
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作者：
Dolinsky, Vernon W.;Rogan, Kyle J.;Dyck, Jason R. B.
由于含多柔比星（DOX）的化疗会导致左心室（LV）功能障碍和重塑，并可能进展为心力衰竭，因此有必要采取减轻DOX心脏毒性的策略来改善癌症患者的健康状况。尽管临床证据表明有氧运动训练（ET）可以预防接受DOX化疗的患者的心脏毒性，但所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治疗对运动能力、LV重塑和抗氧化应激的疗效。将小鼠分为4组，分别给予生理盐水、DOX（8 mg/kg ip，每周1次）、DOX + RESV（4g/kg饲料，自由采食）和DOX + ET（45 min跑台运动，5d/wk），共8 wk。通过在体超声心动图评价左室功能和形态。DOX可引起左室重构不良反应，而适度的ET可部分抑制左室重构，RESV可完全抑制左室重构。这些影响被运动表现的改善所抵消。ET和RESV的心脏保护特性与降低心钠素水平和脂质过氧化副产物4-羟基-2-壬烯醛有关。此外，ET和RESV增加心肌肌质/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，和mitofusin-1和-2在给予DOX的小鼠的表达。与适度ET相比，RESV更有效地防止了DOX诱导的LV重构，并与DOX诱导的氧化应激减少有关。我们的发现对于保护患者免受DOX相关心脏损伤具有重要意义。
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.