Mitochondrial Haplotype Influences LV Dysfunction in Heart Failure

描述（由申请人提供）：二尖瓣和主动脉瓣返流（MR和AR）的容量过载（VO）研究表明，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。在目前的项目中，我们提供了初步数据，证明线粒体内存在基质金属蛋白酶（MMPs），并通过VO激活它们。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偶联和ROS的产生。因此，我们假设C57 mtDNA单倍型在VO中产生更大的心肌细胞氧化应激和生物能量功能障碍，线粒体MMP激活以及肌纤维和线粒体结构的破坏。活性氧可以作为细胞核的信号机制。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VO中不利的左室重塑和功能。我们将使用C57小鼠及其核背景结合C3H mtDNA （C57n:C3Hmt）线粒体核交换（MNX）小鼠，测试C3H mtDNA小鼠是否可以从VO的病理后果中拯救C57，反之亦然C3Hn:C57mt小鼠。1)表征mtDNA单倍型对VO细胞生物能量学和LV功能的影响。2)证明mtDNA单倍型决定了VO中线粒体氧化剂产生的增加，并导致线粒体MMP激活。3)证明mtDNA单倍型影响ACF致VO小鼠左室的核分子炎症反应。本研究利用VO主动脉腔瘘小鼠模型，该模型集成了一种MNX小鼠模型中完整心肌细胞生物能量学和氧化应激测量的新技术，其中一种小鼠品系的线粒体（mt） DNA被纳入另一种小鼠品系的核(n)基因组（例如，C57n:C3Hmt或C3Hn:C57mt）。

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). PUBLIC HEALTH RELEVANCE: 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. Intra- mitochondrial ROS generate a variety of products within the mitochondria which modify mitochondrial proteins and so change their function and activity. Here we test the hypothesis that variations in mitochondrial DNA (mtDNA) can modify the response to stress using novel murine models of mtDNA haplotype.