Mitochondrial fission mediates hypertensive vascular remodeling

项目摘要 高血压的患病率稳步上升，高血压和高血压病的死亡率达到30，221人， 相关肾病。虽然有有效的降压治疗，但潜在的 导致血管重塑和高血压终末器官损害的病理生理学仍然很差 明白线粒体功能障碍与多种心血管疾病有关。但 线粒体质量控制在高血压中的机制和作用尚不清楚。我的初步数据 显示了通过激活动力蛋白相关的GT3，Drp 1，在血管中增强线粒体分裂的作用。 平滑肌细胞（VSMCs）在高血压血管重塑中的作用。100 nM血管紧张素II（AngII）治疗 大鼠主动脉VSMCs诱导短暂的线粒体分裂（最大值在2-4 h）， 氧物种（ROS）的产生。Drp 1的病毒（ad-siDrp 1）和药理学（mdivi 1）抑制减弱 AngII诱导的线粒体分裂以及线粒体ROS生成的增强，总细胞 蛋白质、细胞体积和细胞外胶原含量。在体内，Mdiv 1抑制血管肥大， 血管紧张素Ⅱ（AngII）1000 ng/kg/min处理2周后，在主动脉、心脏和肾脏（C57 BL/6）中诱导血管周围纤维化 小鼠）。Mdivi 1还抑制AngII诱导的左心室肥厚，并降低KDEL和硝基酪氨酸 冠状动脉和肾动脉中的染色表明血管ER应激和氧化应激减弱。我们 报告说，药物抑制Drp 1，防止血管紧张素II诱导的血管重塑。基于这些 研究结果，我建议以下研究来调查我们的中心假设，即线粒体分裂 介导高血压血管重塑。我是由两位优秀的联合私家侦探江口博士和里佐博士训练的 （天普大学），每个人都在血管紧张素信号和血管研究的专业知识。我也将 分别由血管紧张素和线粒体研究领域的领导者Harrison博士（范德比尔特 Sesaki博士（约翰霍普金斯大学）。这个提议会大大促进我的训练 并符合我的职业兴趣，探索心血管病理生理学作为一个医生，科学家， 有助于寻找高血压并发症的新治疗方法。 为了深入了解AngII激活Drp 1的机制及其在VSMC特异性Drp 1-/-小鼠中的作用， 高血压模型，我提出以下目标： 1.通过以下方法研究AngII诱导的线粒体断裂的机制和后果： 靶向Drp 1在体外血管平滑肌细胞（VSMCs）中的表达。 2.检测Drp 1在AngII介导的血管重构和线粒体功能障碍中的作用。

Project Summary The prevalence of hypertension is growing steadily with the mortality reaching 30,221 from hypertensive and associated renal disease. While there is effective blood pressure reduction therapy, the underlying pathophysiology leading to the vascular remodeling and hypertensive end-organ damage remains poorly understood. Mitochondrial dysfunction has been implicated in various cardiovascular diseases. But the mechanism and role of mitochondrial quality control in hypertension is under-investigated. My preliminary data shows a role of enhanced mitochondrial fission via activation of dynamin-related GTPase, Drp1, in vascular smooth muscle cells (VSMCs) in hypertensive vascular remodeling. 100 nM Angiotensin II (AngII) treatment of rat aortic VSMCs induced transient mitochondrial fission (max at 2-4 h) and enhanced mitochondrial reactive oxygen species (ROS) production. Viral (ad-siDrp1) and pharmacological (mdivi1) inhibition of Drp1 attenuated AngII-induced mitochondrial fission as well as enhancement of mitochondrial ROS generation, total cell protein, cell volume and extracellular collagen content. In vivo, Mdivi1 suppressed vascular hypertrophy and perivascular fibrosis induced by 2 weeks AngII treatment (1000ng/kg/min) in aorta, heart and kidney (C57BL/6 mice). Mdivi1 also inhibited AngII-induced left ventricular hypertrophy and reduced KDEL and nitro-tyrosine staining in coronary and renal arteries suggesting attenuation of vascular ER stress and oxidative stress. We report that pharmacological inhibition of Drp1, prevents AngII-induced vascular remodeling. Based on these findings, I am proposing the following study to investigate our central hypothesis that mitochondrial fission mediates hypertensive vascular remodeling. I am trained by excellent co-PIs, Dr. Eguchi and Dr. Rizzo (Temple University), each with expertise in angiotensin signaling and vascular research. I will also be supported by leaders in angiotensin and mitochondrial research fields, respectively, Dr. Harrison (Vanderbilt University) and Dr. Sesaki (John Hopkins University). This proposal would both greatly advance my training and be in line with my career interests to explore cardiovascular pathophysiology as a physician-scientist and contribute to the search for novel treatments for hypertensive complications. To gain mechanistic insight into Drp1 activation by AngII and its effect in VSMC specific Drp1-/- mice in a hypertension model, I propose the following aims: 1. To examine the mechanism and consequences of AngII-induced mitochondrial fragmentation by targeting Drp1 in vascular smooth muscle cell (VSMCs) in vitro. 2. To test the roles of Drp1 in AngII-mediated vascular remodeling and mitochondrial dysfunction in vivo.