以動物模式探討前置性運動訓練介入對放射照射誘發心肌功能異常之成效

Effects of exercise preconditioning on radiation-induced cardiac dysfunction - animal study

張文馨(Wen-Hsin Chang)

指導教授 ： 王儷穎

國立臺灣大學/醫學院/物理治療學研究所/碩士(2019年)

https://doi.org/10.6342/NTU201903761

摘要

研究背景與目的：過去臨床追蹤研究發現，心肌在接受非標的放射照射後，會發生放射性心臟疾病。而在過去動物研究中，前置性有氧運動訓練對如缺血再灌流之心臟損傷具降低傷害之效益；但是否對接受放射照射之心臟也具相似的保護效益並不清楚。因此本研究的目的是以動物模式探討前置性有氧運動訓練是否能預防放射導致的心臟功能異常並探討可能之作用機制。
研究方法：本研究將24隻3至4週大之雄性Wistar大鼠，隨機分配到控制組（Ctrl）、放射組（IR）、運動訓練組（Ex）、及運動放射組（ExIR）（n=6）。Ex及ExIR組進行6週，每週5天，每天60分鐘之運動訓練。IR及ExIR大鼠在ExIR組完成運動訓練後，進行心臟分次放射照射，劑量為2 Gy/天，5天總量共10 Gy。所有大鼠在放射照射（或無照射）完成後一週，以導電心導管進行活體心臟功能測試（壓力-容積分析）。待分析結束後犧牲大鼠，取其左心室組織進行後續生化分析。以γH2AX分析脫氧核醣核酸；蛋白質之氧化傷害則以蛋白質羰基濃度分析；抗氧化能力以CuZnSOD及MnSOD mRNA表現量分析；以Masson's trichrome染色觀察纖維化變化。
結果：相較於對照控制組，放射照射會造成心臟收縮及舒張功能顯著下降（兩者皆p<0.01），γH2AX發生率（Ctrl: 23.3% vs. IR: 38.9%, p<0.01）及蛋白質羰基濃度（Ctrl: 2.3 nmol/mg vs. IR: 3.5 nmol/mg, p<0.01）顯著較高。相較於無運動訓練之對照組，前置性運動訓練後進行放射照射之大鼠，心臟收縮及舒張功能下降之情形顯著較小（兩者皆p<0.01），γH2AX發生率（IR: 38.9% vs. ExIR: 27.3%, p<0.01）及蛋白質羰基濃度（IR: 3.5 nmol/mg vs. ExIR: 2.2 nmol/mg, p<0.01）顯著較低。相較於未訓練的對照組，運動訓練組的CuZnSOD mRNA表現量（IR: 0.3 vs. ExIR: 0.5, p<0.01）及MnSOD mRNA表現量（IR: 0.1 vs. ExIR: 0.9, p<0.01）皆顯著較高。纖維化變化分析在各組之間未見顯著差異。
結論：放射照射後一週會造成心臟收縮及舒張功能異常，而前置性有氧運動訓練可透過正調控心肌之抗氧化能力來達到心臟保護效益。

關鍵字

放射照射 ； 前置性運動訓練 ； 心臟功能 ； 氧化壓力 ； 抗氧化能力

並列摘要

Background and purpose: Clinical studies have reported that cardiac irradiation during treatment of thoracic cancers could lead to radiation-induced heart disease. Exercise preconditioning has been shown to decrease ischemia-reperfusion related cardiac damage in animal studies. Whether exercise preconditioning could ameliorate irradiation induced cardiac injury remains to be determined. The aims of this study were to investigate the effects of preconditioned exercise training on irradiation related cardiac dysfunction and exploring the potential underlying mechanism in animal model.
Methods: A total of 24 adult male Wistar rats aged 3 to 4 week-old were randomized into control (Ctrl), irradiation (IR), exercise training (Ex) and exercise training + irradiation (ExIR) group (n=6 per group). The Ex and ExIR underwent exercise training on a motor-driven treadmill for 60 minutes/day, 5 days/week, for a total of 6 weeks. After anesthetized, rats in IR and ExIR received 2 Gy/day irradiation to the heart region for 5 days (total dose of 10 Gy). In vivo cardiac function (pressure-volume analysis) were examined one week after all designated interventions were complete and left ventricles were excised for biochemical analysis. The mRNA levels of antioxidant enzyme (i.e., CuZnSOD and MnSOD) were determined using quantitative real-time PCR analysis. Retention of γH2AX foci was analyzed and used as an indicator for DNA damage. Level of protein carbonyl was analyzed as an indicator for oxidative injury to protein. Masson’s trichrome staining was used to exam myocardial fibrosis.
Results: Compared to no irradiation Ctrl, cardiac systolic and diastolic function were significantly lower (both p<0.01), γH2AX (Ctrl: 23.3% vs. IR: 38.9%, p<0.01) and protein carbonyl (Ctrl: 2.3 nmol/mg vs. IR: 3.5 nmol/mg, p<0.01) was significantly higher in IR group. Compared to no exercise training, rats in ExIR group had better cardiac systolic and diastolic function (both p<0.01) after irradiation, and had significantly lower γH2AX (IR: 38.9% vs. ExIR: 27.3%, p<0.01) and protein carbonyl (IR: 3.5 nmol/mg vs. ExIR: 2.2 nmol/mg, p<0.01). CuZnSOD mRNA (IR: 0.3 vs. ExIR: 0.5, p<0.01) and MnSOD mRNA (IR: 0.1 vs. ExIR: 0.9, p<0.01) were significantly higher in the ExIR group compared to those of IR group. No apparent fibrotic changes was observed in all experiment groups.
Conclusion: The results of this study showed that exercise preconditioning could ameliorate cardiac dysfunction after irradiation through upregulation its antioxidant capacity.

並列關鍵字

Irradiation ； Exercise training ； Cardiac function ； Oxidative stress ； Antioxidant capacity

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