Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB, UK.
Toxicol Appl Pharmacol. 2013 Apr 15;268(2):149-56. doi: 10.1016/j.taap.2012.12.003. Epub 2012 Dec 20.
Chemotherapeutic agents such as doxorubicin are known to cause or exacerbate cardiovascular cell death when an underlying heart condition is present. However, the mechanism of doxorubicin-induced cardiotoxicity is unclear. Here we assess the cardiotoxic effects of doxorubicin in conditions of myocardial ischaemia reperfusion and the mechanistic basis of protection, in particular the role of the mitochondrial permeability transition pore (mPTP) in such protection. The effects of doxorubicin (1μM)±cyclosporine A (CsA, 0.2μM; inhibits mPTP) were investigated in isolated male Sprague-Dawley rats using Langendorff heart and papillary muscle contraction models subjected to simulated ischaemia and reperfusion injury. Isolated rat cardiac myocytes were used in an oxidative stress model to study the effects of drug treatment on mPTP by confocal microscopy. Western blot analysis evaluated the effects of drug treatment on p-Akt and p-Erk 1/2 levels. Langendorff and the isometric contraction models showed a detrimental effect of doxorubicin throughout reperfusion/reoxygenation as well as increased p-Akt and p-Erk levels. Interestingly, CsA not only reversed the detrimental effects of doxorubicin, but also reduced p-Akt and p-Erk levels. In the sustained oxidative stress assay to study mPTP opening, doxorubicin decreased the time taken to depolarization and hypercontracture, but these effects were delayed in the presence of CsA. Collectively, our data suggest for the first that doxorubicin exacerbates myocardial injury in an ischaemia reperfusion model. If the inhibition of mPTP ameliorates the cardiotoxic effects of doxorubicin, then more selective inhibitors of mPTP should be further investigated for their utility in patients receiving doxorubicin.
化疗药物如阿霉素在存在潜在心脏疾病的情况下已知会导致或加重心血管细胞死亡。然而，阿霉素诱导的心脏毒性的机制尚不清楚。在这里，我们评估了阿霉素在心肌缺血再灌注条件下的心脏毒性作用及其保护的机制基础，特别是线粒体通透性转换孔 (mPTP) 在这种保护中的作用。使用 Langendorff 心脏和乳头肌收缩模型，在模拟缺血和再灌注损伤的情况下，在分离的雄性 Sprague-Dawley 大鼠中研究了阿霉素 (1μM)±环孢菌素 A (CsA，0.2μM；抑制 mPTP) 的作用。使用氧化应激模型在分离的大鼠心肌细胞中研究药物处理对 mPTP 的影响通过共聚焦显微镜。Western blot 分析评估了药物处理对 p-Akt 和 p-Erk 1/2 水平的影响。Langendorff 和等长收缩模型显示阿霉素在再灌注/再氧化过程中产生有害作用，以及 p-Akt 和 p-Erk 水平升高。有趣的是，CsA 不仅逆转了阿霉素的有害作用，而且降低了 p-Akt 和 p-Erk 水平。在研究 mPTP 开放的持续氧化应激测定中，阿霉素缩短了去极化和过度收缩所需的时间，但在 CsA 存在下，这些作用被延迟。总的来说，我们的数据首次表明阿霉素在缺血再灌注模型中加重心肌损伤。如果 mPTP 的抑制改善了阿霉素的心脏毒性作用，那么更具选择性的 mPTP 抑制剂应该进一步研究其在接受阿霉素治疗的患者中的应用。
