Novel Inflammatory Pathway of Aged-Enhanced Atherosclerosis

老年性动脉粥样硬化的新炎症途径

基本信息

批准号：
9266471
负责人：
Daniel Robert Goldstein
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266471
关键词：
Adaptor Signaling Protein Adoptive Transfer Affect Age Aging Aorta Arterial Fatty Streak Atherosclerosis Autophagocytosis Autophagosome Biological Assay Biological Models CCL2 gene Cardiovascular Diseases Cell Aging Cell Culture Techniques Chemotactic Factors Chemotaxis Chronic Consequentialism DNA Development Disabled Persons Disease Exhibits Experimental Models Failure Healthcare Immune Impairment In Vitro Inflammation Inflammatory Inflammatory Response Link Mitochondria Modeling Molecular Monocytosis Mus Muscle Cells Older Population Oxygen Pathway interactions Peripheral Pharmacology Phenotype Play Production Reactive Oxygen Species Recruitment Activity Reporter Risk Risk Factors Role Testing Toll-like receptors Vascular Smooth Muscle Work aged atherogenesis clinical care cohort in vivo Model inflammatory milieu inhibitor/antagonist insight macrophage monocyte new therapeutic target novel novel therapeutics osteopontin public health relevance

项目摘要

DESCRIPTION (provided by applicant): Chronic low-level inflammation is a hallmark of aging. However, the mechanistic links between chronic inflammation and cardiovascular diseases are not fully understood. As aging is one of the strongest independent risk factors for atherosclerosis, understanding this link is of critical importance to the clinical care of our ever increasing population of older people. In an experimental model of atherosclerosis (i.e., LDLr -/- mice), we found that aging leads to larger atherosclerotic lesions; increased production of macrophage chemo-attractants, CCL2 and osteopontin; peripheral monocytosis; and an increase in macrophage recruitment into the aorta. Our prior work demonstrates that without atherosclerosis, aged vascular smooth muscle cells (VSMC) contribute to the aortic inflammatory milieu by producing increased CCL2 and osteopontin. Importantly, we showed that the production of these inflammatory molecules depends on MyD88, an innate immune adaptor protein downstream of the Toll like receptors. We also found that aging impairs autophagosome formation within VSMC and is accompanied by increased mitochondrial mass and reactive oxygen species. Taken together, these findings suggest that damaged mitochondria accumulate in aging VSMC due to reduced autophagy, leading in turn to a buildup of mitochondrial components that activate MyD88 to enhance atherosclerosis. To test this hypothesis, we will use a new model system in which MyD88 is selectively and inducibly deleted within VSMC of aging atherosclerotic prone mice to examine the extent by which MyD88 expression within VSMC controls age-enhanced macrophage recruitment into the aorta and atherosclerosis. We will also use mice in which autophagy is disabled within VSMC, to determine if autophagy in VSMC controls basal inflammation, monocyte recruitment into the aorta, and the development of atherosclerosis. Our proposal will yield critical insights into how aging impacts inflammatory responses in VSMC to enhance atherosclerosis. Our findings may contribute to the development of novel therapies for atherosclerosis in the older population.

描述（由申请人提供）：慢性低水平炎症是衰老的标志。然而，由于衰老是动脉粥样硬化最强烈的独立危险因素之一，因此尚未完全了解慢性炎症与心血管疾病之间的机制联系。对我们的临床护理至关重要在动脉粥样硬化实验模型（即 LDLr -/- 小鼠）中，我们发现衰老会导致更大的动脉粥样硬化病变；巨噬细胞趋化因子、CCL2 和骨桥蛋白的产生增加；我们之前的研究表明，在没有动脉粥样硬化的情况下，老化的血管平滑肌细胞（VSMC）会导致主动脉炎症。重要的是，我们发现这些炎症分子的产生依赖于 Toll 样受体下游的先天免疫接头蛋白 MyD88。综上所述，这些发现表明，由于自噬减少，受损的线粒体在老化的 VSMC 中积聚，进而导致激活线粒体成分的积累。 MyD88 增强动脉粥样硬化为了检验这一假设，我们将使用一种新的模型系统，其中 MyD88 在衰老的动脉粥样硬化易感小鼠的 VSMC 中被选择性和诱导性删除，以检查 VSMC 中 MyD88 的表达控制年龄增强的巨噬细胞招募到血管内的程度。我们还将使用 VSMC 内自噬被禁用的小鼠来确定 VSMC 中的自噬是否控制基础。炎症、单核细胞募集到主动脉以及动脉粥样硬化的发展将有助于了解衰老如何影响血管平滑肌细胞的炎症反应，从而增强动脉粥样硬化。