Oxidative Stress and Heart Failure by Copper Restriction

铜限制导致的氧化应激和心力衰竭

• 批准号: 7463788
• 负责人: Y James KANG
• 金额: $ 46.25万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463788
• 关键词: Address; Adverse effects; Binding; Binding Sites; Calcineurin; Cardiac; Cardiomyopathies; Chelation Therapy; Copper; Defect; Depressed mood; Detection; Diabetes Mellitus; Diet; Dietary Copper; Disease regression; Estrogen Receptors; Event; Functional disorder; Gel Chromatography; Heart; Heart Hypertrophy; Heart failure; High Pressure Liquid Chromatography; Histidine; Human; Hypertrophic Cardiomyopathy; Intake; Intervention; Knock-out; Liver; Liver Dysfunction; Metabolic Diseases; Metabolism; Metallothionein; Minerals; Molecular; Molecular Chaperones; Mus; Mutation; Organ; Oxidative Stress; Pathway interactions; Patients; Population; Prevention; Proteins; Recovery; Research Personnel; Risk; Role; Stress; Supplementation; System; Tamoxifen; Testing; Toxic effect; Transgenic Mice; Zinc; chelation; clinical application; clinically relevant; cytochrome c oxidase; diabetic cardiomyopathy; human study; insight; mouse model; mutant; novel; pressure; programs; promoter; recombinase; response

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.

描述（由申请人提供）：持续的压力超负荷会导致心脏肥大并转变为心力衰竭。主动脉束带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，但我们有证据表明可能涉及矿物质失衡。我们观察到，即使在持续压力超负荷的情况下，将膳食铜（Cu）摄入量从 6 mg Cu/kg 饮食增加到 20 mg/kg 饮食也可以逆转主动脉束带小鼠模型中已确定的肥厚性心肌病。细胞色素 C 氧化酶 (CCO) 活性降低和线粒体病与人类心力衰竭有关。在压力超负荷诱发的心肌病小鼠模型中也发现了相同的 CCO 缺陷和线粒体病，增加膳食铜摄入可恢复 CCO 活性并逆转线粒体病。我们建议这项研究实现以下目标： 目标 1 是探索持续压力超负荷导致 Cu 限制心脏 CCO 的分子机制。我们将检验以下假设：响应于持续压力超负荷产生的氧化应激，Cu 动员和重新分布或流出会导致 Cu 对 CCO 的限制，从而导致 CCO 组装改变并抑制 CCO 活性。目标 2 是确定受抑制的 CCO 活性恢复在铜补充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条件敲除小鼠模型，其中在他莫昔芬治疗下心脏CCO活性可降低50-70%。我们假设，如果 CCO 活性的恢复至关重要，那么补充铜并不能挽救心脏 COX10 敲除或 CCO 缺陷小鼠的衰竭心脏，即使补充铜也可以逆转其他事件的改变，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消退机制。目标 3 是通过检验以下假设来确定铜疗法在心力衰竭患者适当人群中的潜在应用：铜补充应仅限于压力超负荷心肌病，而不适用于糖尿病性心肌病，因为糖尿病会导致肝功能障碍，进而导致铜滞留在系统中，增加铜对心脏和其他器官毒性的风险。因此，补充铜并不是挽救糖尿病心肌病的合适方法。