Toll-like receptor 9 activation by mitochondrial DNA causes vascular injury in hypertension

项目摘要P1，Webb 线粒体DNA激活Toll样受体9导致高血压血管损伤 高血压影响着7500多万美国成年人，通常在最终器官损害中起主要作用 常见于心血管疾病，包括中风、冠状动脉疾病和缺血性肾病。我们的 Proposal提供了一种新的范例，通过线粒体DNA激活天然免疫系统 (MtDNA)导致高血压患者血管收缩增加、血管扩张减少和血管重塑。 了解这一机制可能有助于开发针对免疫系统的新药 治疗血管功能障碍，防止高血压的进展。这项研究将由 新的假设认为，在高血压中，夸大的血管和组织细胞死亡导致mtDNA 通过Toll样受体9(TLR9)触发先天免疫反应，导致血管炎症， 血管收缩、内皮功能障碍和血管重塑。高血压大鼠模型的建立 将使用[自发性高血压大鼠(SHR)]，我们将通过完成三个实验来验证我们的假设 具体目标：1)测试药物抑制细胞坏死可以减弱 高血压血管功能障碍的发展；2)验证TLR9信号激活的假说 导致内皮功能障碍，增强血管收缩，导致动脉硬化；以及3)测试 认为线粒体DNA参与高血压的发生和维持的假说。建议数 整合生理学、药理学、生化、分子和细胞技术的研究将有助于 更好地了解血压对血管功能的影响，以及异常的贡献 TLR9活化对高血压患者血管功能障碍的影响。

PROJECT SUMMARY P1, WEBB Toll-like receptor 9 activation by mitochondrial DNA causes vascular injury in hypertension Hypertension affects over 75 million U.S. adults and plays a major role in the end organ damage commonly seen with cardiovascular diseases, including stroke, coronary artery disease, and ischemic nephropathy. Our proposal provides a new paradigm whereby activation of the innate immune system via mitochondrial DNA (mtDNA) leads to increased vasoconstriction, reduced vasodilation and vascular remodeling in hypertension. Understanding this mechanism may assist in the development of new drugs that target the immune system to treat vascular dysfunction and prevent the progression of hypertension. The research will be guided by the novel hypothesis that in hypertension, exaggerated vascular and tissue cell death give rise to mtDNA that trigger the innate immune response via Toll-like receptor 9 (TLR9) causing vascular inflammation, vasoconstriction, endothelial dysfunction and vascular remodeling. A rat model of hypertension [spontaneously hypertensive rat (SHR)] will be used and we will test our hypothesis by accomplishing three specific aims: 1) test the hypothesis that pharmacological inhibition of cell necrosis attenuates the development of vascular dysfunction in hypertension; 2) test the hypothesis that activation of TLR9 signaling causes endothelial dysfunction, potentiates vasoconstriction and contributes to arterial stiffening; and 3) test the hypothesis that mtDNA contributes to the development and maintenance of hypertension. The proposed studies, integrating physiological, pharmacological, biochemical, molecular and cellular techniques, will help to better understand the effects of blood pressure on vascular function, as well as the contribution of abnormal TLR9 activation to vascular dysfunction characteristic of hypertension.