Oxidative Stress and Heart Failure by Copper Restriction

描述(申请人提供)：持续的压力超负荷会导致心肌肥厚和向心力衰竭的过渡。主动脉缩窄小鼠模型通过持续压力超负荷的机制导致肥厚性心肌病和心力衰竭，但我们有证据表明矿物质失衡可能参与其中。我们观察到，将饲料中铜的摄入量从6 mg/kg增加到20 mg/kg，即使在持续压力超负荷的情况下，也可以逆转主动脉缩窄小鼠模型中已建立的肥厚性心肌病。细胞色素c氧化酶(CCO)活性降低和线粒体病变与人类心力衰竭有关。在压力超负荷性心肌病小鼠模型中也发现了同样的CCO缺陷和线粒体病变，增加饮食铜摄入量，CCO活性恢复，线粒体病变逆转。本研究的目的有以下几个方面：目的1探讨持续压力超负荷导致心脏铜限制CCO的分子机制。我们将验证这一假说，即持续压力超负荷产生的氧化应激导致铜对CCO的限制，导致CCO组装改变和CCO活性抑制。目的2确定受抑制的CCO活性的恢复在补铜诱导的持续压力超负荷心肌病消退中的重要作用。将使用心脏COX10条件性基因敲除小鼠模型，在该模型中，在三苯氧胺治疗下，心脏CCO活性可以降低50%-70%。我们假设，如果CCO活性的恢复是必不可少的，那么补充铜并不能挽救心脏COX10基因敲除或CCO缺陷小鼠衰竭的心脏，即使补充铜也可以逆转其他事件中的变化，包括钙调神经磷酸酶/NFAT、PI3K/Akt和ERK1/2通路，或者可以激活其他心肌病回归机制。目的3是确定铜疗法在适当的心力衰竭患者群体中的潜在应用，通过测试以下假设来确定铜治疗的潜在应用：铜补充应限于压力超负荷心肌病，而不适用于糖尿病心肌病，因为糖尿病会导致肝功能障碍，进而导致铜在系统中滞留，增加铜对心脏和其他器官的毒性风险。因此，补充铜并不是抢救糖尿病心肌病的合适方法。

DESCRIPTION (provided by applicant): Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. The aortic banding mouse model leads to hypertrophic cardiomyopathy and heart failure through the mechanism of sustained pressure overload but we have evidence that mineral imbalance may be involved. We have observed that increasing dietary copper (Cu) intake from 6 mg Cu/kg diet to 20 mg/kg diet can reverse the established hypertrophic cardiomyopathy in the aortic banding mouse model even in the presence of sustained pressure overload. Decreased cytochrome c oxidase (CCO) activity and mitochondriopathy are associated with heart failure in humans. The same CCO defect and mitochondriopathy are also found in the mouse model of pressure overload-induced cardiomyopathy and increasing dietary Cu intake recovered CCO activity and reversed mitochondriopathy. We propose this study to carry out the following aims: Aim 1 is to explore molecular mechanism by which sustained pressure overload causes Cu restriction to CCO in the heart. We will test the hypothesis that Cu mobilization and redistribution or efflux in response to oxidative stress generated by sustained pressure overload leads to Cu restriction to CCO, resulting in altered CCO assembly and suppressed CCO activity. Aim 2 is to determine the essential role of recovery of suppressed CCO activity in Cu supplementation-induced regression of cardiomyopathy by sustained pressure overload. A cardiac COX10 conditional knockout mouse model in which cardiac CCO activity can be reduced by 50- 70% under the treatment with tamoxifen will be used. We hypothesize that Cu supplementation would not rescue the failing heart in the cardiac COX10-knockout or CCO-deficient mice if the recovery of CCO activity is essential, even Cu supplementation can reverse alterations in other events including calcineurin/NFAT, PI3K/Akt, and ERK1/2 pathways or can activate other cardiomyopathy regression mechanisms. Aim 3 is to define potential application of Cu therapy to appropriate populations of heart failure patients by testing the hypothesis that Cu supplementation should be limited to pressure overload cardiomyopathy, not applied to diabetic cardiomyopathy because diabetes causes liver dysfunction, which in turn causes Cu retention in the system, increasing the risk of Cu toxicity to the heart and other organs. Therefore, Cu supplementation is not an appropriate approach to rescue diabetic cardiomyopathy.