Novel Inflammatory Pathway of Aged-Enhanced Atherosclerosis

 描述(申请人提供)：慢性低水平炎症是衰老的标志。然而，慢性炎症和心血管疾病之间的机制联系并不完全清楚。由于衰老是动脉粥样硬化最强烈的独立危险因素之一，了解这种联系对我们的临床护理至关重要。 老年人口不断增加。在动脉粥样硬化的实验模型(即LDLR-/-小鼠)中，我们发现衰老导致更大的动脉粥样硬化病变；巨噬细胞化学吸引剂CCL2和骨桥蛋白的产生增加；外周单核细胞增多；巨噬细胞向主动脉中募集增加。我们先前的工作表明，在没有动脉粥样硬化的情况下，衰老的血管平滑肌细胞(VSMC)通过产生更多的CCL2和骨桥蛋白来促进主动脉炎症环境。重要的是，我们证明了这些炎症分子的产生依赖于MyD88，MyD88是Toll样受体下游的一种天然免疫适配器蛋白。我们还发现，衰老损害了VSMC内自噬小体的形成，并伴随着线粒体质量和活性氧的增加。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中积累，进而导致线粒体成分的积聚，激活MyD88以加强动脉粥样硬化。为了验证这一假设，我们将使用一种新的模型系统，在该系统中，MyD88选择性地和可诱导地在易发生动脉粥样硬化的衰老小鼠的VSMC中被删除，以检查VSMC中MyD88的表达在多大程度上控制了年龄增强的巨噬细胞重新聚集到主动脉和动脉粥样硬化中。我们还将使用VSMC中自噬被禁用的小鼠，以确定VSMC中的自噬是否控制基础炎症、单核细胞重新进入主动脉和动脉粥样硬化的发展。我们的提案将对衰老如何影响VSMC的炎症反应以增强动脉粥样硬化产生关键的见解。我们的发现可能有助于开发老年人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.