Novel Inflammatory Pathway of Aged-Enhanced Atherosclerosis

 描述（由申请人提供）：慢性低水平炎症是衰老的标志。然而，慢性炎症与心血管疾病之间的机制联系尚不完全清楚。由于衰老是动脉粥样硬化最强烈的独立危险因素之一，因此了解这种联系对于我们有史以来的临床护理至关重要。 老年人口不断增加。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；增加巨噬细胞化学引诱剂、CCL2 和骨桥蛋白的产生；外周单核细胞增多症；以及巨噬细胞招募到主动脉的增加。我们之前的工作表明，在没有动脉粥样硬化的情况下，老化的血管平滑肌细胞 (VSMC) 通过产生增加的 CCL2 和骨桥蛋白而导致主动脉炎症环境。重要的是，我们发现这些炎症分子的产生取决于 MyD88，这是 Toll 样受体下游的先天免疫接头蛋白。我们还发现，衰老会损害 VSMC 内自噬体的形成，并伴有线粒体质量和活性氧的增加。总而言之，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，进而导致线粒体成分的积累，从而激活 MyD88，从而加剧动脉粥样硬化。为了检验这一假设，我们将使用一个新的模型系统，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主动脉和动脉粥样硬化的程度。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底炎症、单核细胞募集到主动脉以及动脉粥样硬化的发展。我们的提案将对衰老如何影响 VSMC 中的炎症反应以增强动脉粥样硬化产生重要见解。我们的发现可能有助于开发治疗老年人群动脉粥样硬化的新疗法。

 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.