Mechanisms of PCSK9 in endothelial aging

项目摘要/摘要 心脑血管疾病是全球死亡的主要原因， 根据世界卫生组织关于非传染性疾病的全球状况报告，三分之一的死亡人数 疾病。内皮细胞衰老和随后的内皮衰老密切相关 老年人心脑血管疾病。PCSK9是一种丝氨酸蛋白酶，它在 在调节炎症反应和程序性细胞死亡中的作用。我们最近报道了PCSK9 导致线粒体DNA损伤、NLRP3炎症小体激活和下垂(一种炎症性疾病 细胞程序性死亡)，导致促炎细胞因子IL-1β和IL-18的释放。此外, 我们发现，MerTK，一个泡吞噬的标志，在年轻的内皮细胞中高表达，而在 吞噬作用是吞噬细胞清除凋亡细胞的一个重要过程。 根据我们的初步研究，这个项目要检验的中心假设是，衰老介导的PCSK9 上调会损害气泡吞噬功能，表现为无法清除凋亡细胞，导致下垂，以及 促进内皮细胞衰老和随后的内皮老化。我们的长期目标是解剖 PCSK9与泡腾功能受损、上行性下垂的关系及其在发育中的作用 血管内皮细胞老化。我们的具体目标是：目标1-确定内皮细胞分泌的PCSK9的贡献 目标2-确定PCSK9在调节胞吐作用中的作用；以及目标3-定义PCSK9的作用 PCSK9在调节下垂中的作用。拟议的研究具有创新性，因为它将把PCSK9与 内皮细胞泡泡吞噬功能受损和上皮性上睑下垂及内皮细胞的作用 细胞分泌的PCSK9对血管内皮细胞衰老的影响。深入了解线粒体DNA损伤的新机制可能会 确定针对线粒体DNA损伤的药物设计的新想法，以控制受损的泡腾作用。

PROJECT SUMMARY/ABSTRACT Cardiovascular and cerebrovascular diseases are the leading cause of global deaths contributing to as much as one third of deaths, according to the World Health Organization's Global Status Report on Noncommunicable Diseases. Endothelial cell senescence and subsequent endothelial aging are closely associated with cardiovascular and cerebrovascular diseases in older people. PCSK9 is a serine protease that plays an important role in regulating inflammatory responses and programmed cell death. We recently reported that PCSK9 contributes to mitochondrial DNA damage, NLRP3 inflammasome activation, and pyroptosis (an inflammatory form of programmed cell death), leading to the release of pro-inflammatory cytokines IL-1β and IL-18. In addition, we found that MerTK, a marker for efferocytosis, is highly expressed in young endothelial cells while inhibited in old endothelial cells; efferocytosis is an important process by which apoptotic cells are removed by phagocytes. Based on our preliminary studies, the central hypothesis to be tested in this project is that aging-mediated PCSK9 upregulation impairs efferocytosis showing failed clearance of apoptotic cells, induces pyroptosis, and contributes to endothelial cell senescence and subsequent endothelial aging. Our long-term goal is to dissect the relationship between PCSK9, impaired efferocytosis, upregulated pyroptosis, and its role in the development of endothelial aging. Our specific aims are: Aim 1 - Determine the contribution of endothelial cell-secreted PCSK9 to endothelial aging; Aim 2 - Define the role of PCSK9 in regulating efferocytosis; and Aim 3 - Define the role of PCSK9 in regulating pyroptosis. The proposed research is innovative because it will connect PCSK9 with impaired efferocytosis and upregulated pyroptosis in endothelial cells and evaluate the contribution of endothelial cell-secreted PCSK9 to endothelial aging. Insight into the novel mechanism of mitochondrial DNA damage may identify novel ideas for drugs designed to control impaired efferocytosis, targeted at mtDNA damage.