Oxidative Stress and Heart Failure by Copper Restriction

描述（由申请人提供）：持续压力超负荷导致心脏肥大并转变为心力衰竭。主动脉结扎小鼠模型通过持续压力超负荷机制导致肥厚型心肌病和心力衰竭，但我们有证据表明可能涉及矿物质失衡。我们已经观察到，将膳食铜（Cu）摄入量从6 mg Cu/kg膳食增加到20 mg/kg膳食可以逆转主动脉结扎小鼠模型中建立的肥厚型心肌病，即使在持续压力超负荷的情况下。细胞色素c氧化酶（CCO）活性降低和心肌病与人类心力衰竭相关。在压力超负荷性心肌病小鼠模型中也发现了相同的CCO缺陷和心肌病，增加膳食铜摄入量可恢复CCO活性并逆转心肌病。本研究的主要目的是：目的1：探讨持续性压力超负荷引起心脏Cu对CCO限制的分子机制。我们将测试的假设，铜动员和再分配或流出，在持续的压力过载产生的氧化应激导致铜限制CCO，导致CCO组装改变和抑制CCO活性。目的2是确定恢复抑制CCO活性在持续压力超负荷的铜中毒诱导的心肌病消退中的重要作用。将使用心脏COX 10条件性敲除小鼠模型，其中心脏CCO活性在他莫昔芬治疗下可降低50- 70%。我们假设，如果CCO活性的恢复是必不可少的，补充铜不会拯救心脏COX 10基因敲除或CCO缺陷小鼠的衰竭心脏，即使补充铜可以逆转其他事件的改变，包括钙调神经磷酸酶/NFAT，PI 3 K/Akt和ERK 1/2途径，或可以激活其他心肌病消退机制。目的3是通过测试以下假设来确定铜治疗在适当的心力衰竭患者人群中的潜在应用：铜补充应仅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，这反过来会导致铜滞留在系统中，增加心脏和其他器官的铜毒性风险。因此，补充铜不是一种合适的方法来挽救糖尿病心肌病。

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.