Mechanisms of Redox Mediated Cardioprotection

描述：（由申请人提供）本研究的目的是确定 在癌症治疗期间导致心脏保护的新机制。在 心脏组织，细胞毒性和细胞保护作用都涉及在 肿瘤坏死因子α（TNF α）的作用。虽然各种癌症 已经显示治疗剂诱导TNF α的快速表达， 两种类型的TNF受体（p55和p75）都在心肌细胞中表达， 这种细胞因子及其相关受体在心脏对 癌症治疗是未知的。抗雌激素他莫昔芬（TAM）已被证明， 不仅在减少对侧乳房方面具有有益效果， 癌症，而且还导致癌症中心脏病的发病率降低 患者他莫昔芬通常被认为是一种抗雌激素， 抑制肿瘤生长。然而，观察到的心脏保护作用 各种临床试验表明， 抗雌激素很复杂，不能简单地描述为缺乏雌激素 TNF受体对ADR诱导的心脏损伤更敏感， 用TAM预处理导致p75 TNF的剂量依赖性降低， 受体和抑制TNF α诱导的线粒体损伤。这些 结果表明，低水平的内源性TNF可能具有心脏保护作用 而高水平的TNF α是心脏毒性的。我们假设：（1） 内源性TNF α通过快速激活 块我们的初步数据表明，缺乏核因子的突变小鼠 κ β（NF κ β），随后诱导保护性蛋白; 2）高 TNF α水平引起过度的TNF受体介导的 线粒体损伤; 3）线粒体抗氧化能力增强 改善TAM诱导的心脏保护作用。肿瘤坏死因子α和三羟甲基氨基甲烷在心肌梗死中的作用 将在动物中建立损伤，分离线粒体，并分离 心肌细胞转基因动物将被用于研究 TNF/TAM与线粒体抗氧化状态在心脏保护中的联系 拟议的研究将提供有关作用的基本信息， TNF和TAM在心脏损伤中的作用。研究结果还应提供以下方面的见解： 线粒体抗氧化状态和TAM之间的联系。结果可能 导致制定选择性方法来改善对 心脏，从而降低自由基相关抗癌药物的毒性 剂.

DESCRIPTION: (provided by applicant) The goal of this study is to identify novel mechanisms leading to cardioprotection during cancer treatment. In cardiac tissue, both cytotoxic and cytoprotective actions are implicated in the action of tumor necrosis factor alpha (TNFalpha). Although a variety of cancer therapeutic agents have been shown to induce rapid expression of TNFalpha and both types of TNF receptors (p55 and p75) are expressed in cardiomyocytes, the role of this cytokine and its associated receptors in cardiac response to cancer therapy is unknown. The anti-estrogen tamoxifen (TAM) has been shown to have a beneficial effect not only in the reduction of contralateral breast cancer but also to result in a reduced incidence of heart disease in cancer patients. Tamoxifen is generally thought to act as an anti-estrogen in breast cancer to inhibit tumor growth. However, the cardioprotective effect observed in various clinical trials suggests that the mechanism of action of anti-estrogens is complex and cannot be described simply as an estrogen lacking TNF receptors are more sensitive to ADR-induced cardiac injury and that pre-treatment with TAM results in a dose-dependent reduction of the p75 TNF receptor and suppression of TNFalpha-induced mitochondrial injury. These results suggest that low levels of endogenous TNF may be cardioprotective whereas high levels of TNFalpha are cardiotoxic. We hypothesized that 1) endogenous TNFalpha serves a cardioprotective role by rapid activation of the block. Our preliminary data indicate that mutant mice lacking nuclear factor kappa Beta (NFkBeta) with subsequent induction of protective proteins; 2) high levels of TNFalpha cause excessive TNF-receptors mediated-induction of mitochondrial injury; and 3) enhancement of mitochondrial antioxidant capacity improves TAM-induced cardioprotection. The role of TNFalpha and TAM in cardiac injury will be established in animals, isolated mitochondria, and isolated cardiomyocytes. Genetically modified animals will be used to investigate the link between TNF/TAM and mitochondrial antioxidant status in cardioprotection. The proposed studies will provide fundamental information concerning the role of TNF and TAM in cardiac injury. The results should also provide insights into the link between mitochondrial antioxidant status and TAM. The results could lead to the development of selective approaches to improve protection of the heart, thus reducing the toxicity of free radical-associated anti-cancer agents.