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

项目概要P1，网络 线粒体DNA激活Toll样受体9导致高血压血管损伤 高血压影响超过7500万美国成年人，通常在终末器官损伤中起主要作用。 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 一项提案提供了一种新的范例，通过线粒体DNA激活先天免疫系统， 线粒体DNA（mtDNA）的缺失导致高血压中血管收缩增加、血管舒张减少和血管重塑。 了解这种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，防止高血压的发展。这项研究将由 一种新的假说，即在高血压中，过度的血管和组织细胞死亡引起mtDNA， 通过Toll样受体9（TLR 9）触发先天免疫应答，引起血管炎症， 血管收缩、内皮功能障碍和血管重塑。高血压大鼠模型 [自发性高血压大鼠（SHR）]将被使用，我们将测试我们的假设，通过完成三个 具体目的：1）测试药理学抑制细胞坏死减弱细胞凋亡的假设， 高血压中血管功能障碍的发展; 2）测试TLR 9信号传导的激活 导致内皮功能障碍，增强血管收缩，并有助于动脉硬化;和3）测试 线粒体DNA与高血压的发展和维持有关的假说。拟议 综合生理学、药理学、生物化学、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，以及异常血压的贡献。 TLR 9活化对高血压特征性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.