Mitochondrial Haplotype Influences LV Dysfunction in Heart Failure

线粒体单倍型影响心力衰竭中的左心室功能障碍

• 批准号: 8645719
• 负责人: VICTOR M DARLEY-USMAR
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645719
• 关键词: Adult; Affect; Aortic Valve Insufficiency; Back; Bioenergetics; Cardiac Myocytes; Cell Nucleus; Code; Coupling; DNA Sequence; Data; Disease susceptibility; Electron Transport; Event; Failure; Fistula; Functional disorder; Gene Expression; Generations; Genes; Genome; Haplotypes; Heart; Heart failure; In Vitro; Inbred C3H Mice; Inflammatory; Inflammatory Response; Lead; Left Ventricular Remodeling; Matrix Metalloproteinases; Measurement; Mediating; Mitochondria; Mitochondrial DNA; Mitochondrial Matrix; Mitochondrial Proteins; Mitochondrial Swelling; Mitral Valve Insufficiency; Modeling; Molecular; Mouse Strains; Mus; Myofibrils; Nitrogen; Nuclear; Oxidants; Oxidative Stress; Oxygen; Pathologic; Patients; Phenotype; Play; Production; Proteins; Protons; Renin-Angiotensin System; Role; Signal Transduction; Stress; Stretching; Structure; Testing; Variant; Vasodilator Agents; extracellular; improved; in vivo; insight; mouse model; new technology; novel; research study; response

DESCRIPTION (provided by applicant): Studies of volume overload (VO) of mitral and aortic regurgitation (MR and AR) show no benefit on LV remodeling using vasodilator drugs or renin-angiotensin system blockade. In the current project, we present preliminary data demonstrating the existence of matrix metalloproteinases (MMPs) within mitochondria and their activation with VO. The mitochondrial (mt) DNA haplotype of C57BL/6J compared to that of C3h/HeN mice have higher proton coupling and ROS generation. Therefore we hypothesize that the C57 mtDNA haplotype produces greater cardiomyocyte oxidative stress and bioenergetic dysfunction, mitochondrial MMP activation, and disruption of myofibrillar and mitochondrial structure in VO. ROS can act as signaling mechanisms to the nucleus. We also hypothesize that mitochondrial haplotype directs nuclear molecular signals that also produce a greater molecular inflammatory response and predict adverse LV remodeling and function in VO. We will use the C57 mouse with its nuclear background combined with C3H mtDNA (C57n:C3Hmt) mitochondrial nuclear exchange (MNX) mouse, to test whether mice with C3H mtDNA can rescue C57 from pathologic consequences of VO and vice versa in C3Hn:C57mt mice in the following specific aims. 1) Characterize the impact of mtDNA haplotype on cellular bioenergetics and LV function in VO. 2) Demonstrate that mtDNA haplotype determines increased mitochondrial oxidant production in VO and causes mitochondrial MMP activation. 3) Demonstrate that mtDNA haplotype influences nuclear molecular inflammatory response in the LV of mice subjected to the VO of ACF. This proposal with utilize the aortocaval fistula mouse model of VO, which integrates novel technology of measurements of bioenergetics of intact cardiomyocytes and oxidative stress in a MNX mouse model in which the mitochondrial (mt) DNA of one mouse strain is incorporated into the nuclear (n) genome of another (e.g., C57n:C3Hmt or C3Hn:C57mt).

描述（由申请人提供）：二尖瓣和主动脉反流（MR和AR）体积超负荷（VO）的研究表明，使用血管扩张剂药物或肾素 - 血管紧张素系统阻断对LV重塑没有任何好处。在当前项目中，我们提供了初步数据，证明了线粒体内基质金属蛋白酶（MMP）的存在及其用VO的激活。与C3H/HEN小鼠相比，C57BL/6J的线粒体（MT）DNA单倍型具有较高的质子偶联和ROS产生。因此，我们假设C57 mtDNA单倍型会产生更大的心肌细胞氧化应激和生物能功能障碍，线粒体MMP激活以及肌原纤维纤维和线粒体结构的破坏。 ROS可以充当核的信号传导机制。我们还假设线粒体单倍型指导核分子信号，该信号也产生更大的分子炎症反应，并预测VO中的不良LV重塑和功能。我们将使用具有核背景的C57小鼠以及C3H mtDNA（C57N：C3HMT）线粒体核交换（MNX）小鼠的结合，测试使用C3H mtDNA的小鼠是否可以从C3HN：C3HN：C57MT鼠标中的VO和VICE的病理后果中挽救C57的小鼠。 1）表征mtDNA单倍型对VO中细胞生物能学和LV功能的影响。 2）证明mtDNA单倍型决定了VO中的线粒体氧化剂产生的增加，并引起线粒体MMP激活。 3）证明mtDNA单倍型会影响受ACF VO的小鼠LV的核分子炎症反应。这项提出的提议利用了VO的主动脉腔瘘小鼠模型，该模型整合了MNX小鼠模型中完整心肌细胞和氧化应激的生物能力测量技术的新技术，其中将一个小鼠菌株的线粒体（MT）DNA纳入了核（N）基因（n）基因（例如，c5）或c3 c5 nhh，c3 hhem c3 hh of nouge（n）基因（n）。