Mitochondrial Haplotype Influences LV Dysfunction in Heart Failure

描述(由申请人提供)：关于二尖瓣和主动脉瓣返流(MR和AR)的容量超负荷(VO)的研究表明，使用血管扩张剂药物或肾素-血管紧张素系统阻滞剂对左室重构没有好处。在目前的项目中，我们提供了初步的数据，证明了线粒体中存在基质金属蛋白酶(MMPs)，并用VO激活了它们。与C3H/HEN小鼠相比，C57BL/6J小鼠线粒体(Mt)DNA单倍型具有更高的质子偶联和ROS生成。因此，我们假设C57mtDNA单倍型在VO中引起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，以及肌原纤维和线粒体结构的破坏。ROS可以作为核内的信号机制。我们还假设，线粒体单倍型引导核分子信号，也产生更大的分子炎症反应，并预测VO患者不利的左室重构和功能。我们将使用C57小鼠及其核背景结合C3Hn：C3Hmt)线粒体核交换(MNX)小鼠，在以下特定目标下测试C3Hn：C57mt小鼠是否能使C57免于VO的病理后果，反之亦然。1)研究线粒体DNA单倍型对VO细胞生物能量学和左心室功能的影响。2)证实线粒体DNA单倍型决定了VO线粒体氧化剂的生成增加，并导致线粒体基质金属蛋白酶的激活。3)证实线粒体DNA单倍型影响急性冠脉综合征小鼠左室核分子炎症反应。这一建议利用了VO的动静脉瘘小鼠模型，该模型集成了测量完整心肌细胞的生物能量学和MNX小鼠模型中氧化应激的新技术，在MNX小鼠模型中，一个小鼠品系的线粒体(MT)DNA被整合到另一个品系(例如C57n：C3Hmt或C3Hn：C57mt)的核(N)基因组中。 公共卫生相关性：关于二尖瓣和主动脉瓣返流(MR和AR)的容量超负荷(VO)的研究表明，使用血管扩张剂或肾素-血管紧张素系统阻滞剂对左室重构没有好处。线粒体内的ROS在线粒体内产生各种产物，这些产物改变线粒体蛋白，从而改变其功能和活性。在这里，我们使用mtDNA单倍型的新小鼠模型来检验线粒体DNA(MtDNA)的变异可以改变对压力的反应的假设。

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.