MbSOD in chemotherapeutic-Induced Cardiac Injury

空间 提供了 心脏病是使用蒽环类药物作为成分的癌症治疗的主要剂量限制因素 的协议。活性氧（ROS）的产生与大量的 许多治疗剂，包括含有氧化还原循环基团的那些。本研究的目的是 以确定在癌症治疗期间导致心脏保护的新机制。我们对动物的研究 和分离的心肌细胞表明线粒体抗氧化酶的过度表达 含锰超氧化物歧化酶（MnSOD）保护心脏免受阿霉素（ADR）诱导的 心脏损伤有趣的是，ADR治疗导致肿瘤坏死因子循环水平的增加， α（TNF）t是一种多效性细胞因子，也显示产生ROS。我们还发现ADR- 诱导的心脏损伤与p53向线粒体的移位以及p53与 MnSOD。基于这些新的发现，我们假设ADR毒性是级联反应的结果， 涉及ADR产生直接氧化应激，继而导致TNF产生和 线粒体中的氧化应激。为了验证这一假设，从心肌组织和心肌细胞中分离出 MnSOD缺陷型、野生型和过表达MnSOD以及p53缺陷型、p53缺陷型 MnSOD缺陷型和p53缺陷型过表达MnSOD的相同近交系小鼠将被 用作模型。目的1和2将检验ADR毒性是级联反应的结果这一假设， 涉及ADR及其代谢产物产生直接氧化应激，继而导致TNF产生 以及心脏组织和心肌细胞中氧化应激的放大。目标3将检验假设 线粒体中引发的氧化应激作为死亡信号，调节p53易位， 其细胞介导的转录依赖性和非依赖性途径。目标4将测试 细胞抗氧化状态或TNF水平选择性调节改变ADR诱导的心脏 实验性治疗环境中的损伤。这些研究的结果将提供重要的见解， 基于机制的药理学干预，以减少癌症治疗相关的心脏损伤。 由于ADR的广泛使用，这些发现的翻译不仅可以改善生活质量， 也将提高大量癌症患者的无癌生存概率。

SPACE PROVIDED. Heart disease is a major dose limiting factor of cancer therapy that uses anthracycline as a component of the protocol. Generation of reactive oxygen species (ROS) has been implicated in the toxicity of a large number of therapeutic agents including those containing the redox cycling groups. The goal of this study is to identify novel mechanisms that lead to cardioprotection during cancer treatment. Our studies of animal and isolated cardiomyocytes indicate that overexpression of the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) protects the heart against adriamycin (ADR)-induced cardiac injury. Interestingly, ADR treatment leads to an increase in circulating levels of tumor necrosis factor alpha (TNF)t a pleiotropic cytokine that has also been shown to produce ROS. We also found that ADR- induced cardiac injury is associated with translocation of p53 to the mitochondria and interaction of p53 with MnSOD. Based on these novel findings we hypothesize that ADR toxicity is the result of a cascade that involves ADR producing direct oxidative stress that sequentially leads to TNF production and amplification of oxidative stress in mitochondria. To test this hypothesis, cardiac tissue and cardiomyocytes isolated from MnSOD deficient, wild type, and mice overexpressing MnSOD as well as p53 deficient, p53 deficient with MnSOD deficient, and p53 deficient overexpressing MnSOD mice of the same inbred background will be used as models. Aims 1 and 2 will test the hypothesis that ADR toxicity is the result of a cascade that involves ADR and its metabolites producing direct oxidative stress that sequentially leads to TNF production and amplification of oxidative stress in heart tissues and in cardiomyocytes. Aim 3 will test the hypothesis that oxidative stress initiated in mitochondria serves as a death signal, which regulates p53 translocation and its mitochondrial-mediated transcription dependent and independent pathways . Aim 4 will test the hypothesis that selective modulation of cellular antioxidant status or TNF levels alters ADR-induced cardiac njury in experimental therapeutic settings. The results from these studies will provide important insights for mechanistic-based pharmacological interventions to reduce cancer therapy-associated cardiac injury. Because the extensive use of ADR, translation of these findings will not only improve the quality of life but will also enhance the probability of cancer free survival for a large number of cancer patients.