Complement, Cardiovascular Disease, and SLE

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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.