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: 8458082
• 负责人: VICTOR M DARLEY-USMAR
• 金额: $ 34.87万
• 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/8458082
• 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）：二尖瓣和主动脉瓣反流（MR 和 AR）的容量超负荷（VO）研究显示，使用血管扩张药物或肾素-血管紧张素系统阻断对左室重塑没有益处。在当前的项目中，我们提供了初步数据，证明线粒体内基质金属蛋白酶 (MMP) 的存在及其通过 VO 的激活。与 C3h/HeN 小鼠相比，C57BL/6J 的线粒体 (mt) DNA 单倍型具有更高的质子耦合和 ROS 生成。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 VO 中肌原纤维和线粒体结构的破坏。 ROS 可以充当细胞核的信号传导机制。我们还假设线粒体单倍型指导核分子信号，这些信号也会产生更大的分子炎症反应并预测不良的 LV 重塑和 VO 功能。我们将使用核背景结合 C3H mtDNA (C57n:C3Hmt) 线粒体核交换 (MNX) 小鼠的 C57 小鼠，测试具有 C3H mtDNA 的小鼠是否可以在 C3Hn:C57mt 小鼠中拯救 C57 免受 VO 的病理后果，反之亦然。 1) 表征 VO 中 mtDNA 单倍型对细胞生物能学和 LV 功能的影响。 2) 证明 mtDNA 单倍型决定 VO 中线粒体氧化剂产量的增加并导致线粒体 MMP 激活。 3) 证明 mtDNA 单倍型影响接受 ACF VO 的小鼠 LV 中的核分子炎症反应。该提案利用了 VO 的主动脉腔静脉瘘小鼠模型，该模型在 MNX 小鼠模型中集成了测量完整心肌细胞生物能和氧化应激的新技术，其中一种小鼠品系的线粒体 (mt) DNA 被整合到另一种小鼠品系的核 (n) 基因组中（例如，C57n:C3Hmt 或 C3Hn:C57mt）。