Complement, Cardiovascular Disease, and SLE

描述(由申请人提供)： 炎症现在被认为是动脉粥样硬化斑块形成和破裂的关键过程，也是心血管疾病导致的发病率和死亡率的关键。最近的研究也表明，在系统性红斑狼疮患者中，这一过程可能会加速和夸大。我们最近建立了一个专注于血管生物学和病理学的研究计划，重点放在狼疮作为加速动脉粥样硬化的模型。这些研究的刺激因素是Manzi和他的同事最近的一项令人惊讶的观察，他们证明了绝经前SLE女性血清C3和C4水平的升高与主动脉僵硬之间存在强烈的线性关联。虽然血清C3和C4水平的降低传统上被用来监测SLE患者的疾病活动性，但血清补体成分水平的升高与任何疾病过程的关联都是史无前例的。这一观察使我们研究了补体C3和C4在系统性红斑狼疮心血管疾病免疫发病机制中的潜在作用(S)。血管成像研究导致了几个有趣和意想不到的观察，将在这里进一步探索。首先，我们发现补体成分C3和C4在人类和小鼠的动脉壁中以几种不同的模式存在。具体地说，C3和C4的蛋白分解片段与动脉壁内的弹性蛋白共定位，并可能共价结合到弹性蛋白上。这一完全出乎意料的观察表明，动脉壁内的补体沉积可能通过直接干扰弹性纤维的弹性而增加血管僵硬，这是动脉粥样硬化的早期事件。其次，我们观察到补体在血管壁内的聚集沉积，这是斑块形成的已知起点。第三，与对照组相比，我们证明了补体成分在狼疮样综合征小鼠的血管系统中具有特异性。这些观察，加上Manzi及其同事的观察，导致了以下具体目标，这些目标基于我们的中心假设，即补体系统可能影响血管僵硬，并通过直接降低动脉壁内的血管弹性而显著促进动脉粥样硬化过程。这项建议的长期目标是利用正常和异常的人类和小鼠血管系统，对补体系统在动脉粥样硬化中的作用进行初步表征。具体目标1是描述补体蛋白C3和C4在动脉壁内的空间和时间定位。具体目标2是确定补体C3和C4在动脉树中的分布。具体目标3是确定动脉壁内补体C3和C4增加动脉僵硬的能力。这些研究将是首次对补体系统在动脉粥样硬化中的作用进行严格的研究，使用SLE作为加速冠状动脉血管疾病的模型。最终，拟议研究产生的数据应该确定SLE和动脉粥样硬化的治疗靶点。

DESCRIPTION (provided by applicant): Inflammation is now recognized as a critical process in the development and rupture of atherosclerotic plaques, and in the morbidity and mortality that result from cardiovascular disease. Recent studies have also suggested that this process may be accelerated and exaggerated in patients with systemic lupus erythematosus. We have recently established a research program focused on vascular biology and pathology, with a focus on lupus as a model of accelerated atherosclerosis. The stimulus for these investigations was a recent surprising observation by Manzi and colleagues who demonstrated a strong linear association between elevated serum levels of C3 and C4 and aortic stiffness in premenopausal women with SLE. Whereas decreased serum levels of C3 and C4 have traditionally been used to monitor disease activity in patients with SLE, association of elevated serum levels of serum complement components with any disease process is unprecedented. This observation led us to investigate the potential role(s) for complement C3 and C4 in the immunopathogenesis of cardiovascular disease in SLE. Vascular imaging studies led to several intriguing and unexpected observations that will be further explored here. First, we discovered that complement components C3 and C4 are present in several distinct patterns within the arterial walls of both humans and mice. Specifically, proteolytic fragments of C3 and C4 co-localize with, and may be covalently bound to, elastin within the arterial wall. This entirely unexpected observation suggested that complement deposition within the arterial wall may increase vascular stiffness, an early event in atherosclerosis, through direct interference with elastic fiber flexibility. Second, we observed aggregates of complement deposition within the vessel wall, the site at which plaque formation is now known to initiate. Third, we demonstrated that complement components are specifically present within the vasculature of mice with lupus-like syndromes as compared with controls. These observations, together with those of Manzi and colleagues, have led to the following specific aims that are based on our central hypothesis that the complement system may influence vascular stiffness and contribute significantly to the atherosclerotic process by directly reducing vascular elasticity within the arterial wall. The long-term goal of this proposal is to perform an initial characterization of the role of the complement system in atherosclerosis, using normal and abnormal human and mouse vascular systems. Specific Aim 1 is to characterize the spatial and temporal localization of complement proteins C3 and C4 within the arterial wall. Specific Aim 2 is to characterize the distribution of complement C3 and C4 within the arterial tree. Specific Aim 3 is to determine the capacity of complement C3 and C4 within the arterial wall to increase arterial stiffness. These studies will represent the first rigorous investigation of the role of the complement system in atherosclerosis, using SLE as a model of accelerated coronary vascular disease. Ultimately, the data generated by the proposed studies should identify therapeutic targets in SLE and in atherosclerosis in general.