(Verbatim from the application): Premature cardiovascular disease is a major cause of mortality in systemic lupus erythematosus (SLE) with the risk of myocardial infarction increased up to 50-fold. The mechanisms underlying accelerated atherosclerosis in SLE are poorly understood. Recent studies indicate that inflammation, through the effects of inflammatory cytokines, and oxidative stress, through lipid peroxidation, play important roles in the pathogenesis of atherosclerosis. We postulate that accelerated, inflammation-promoted atherosclerosis occurs in SLE through these mechanisms. Thus, we propose to test the hypotheses: 1) that structural and functional vascular damage is more frequent and more severe in patients with SLE than matched controls and 2) that this impairment of vascular integrity is associated with clinical and laboratory markers of inflammation, plasma homocysteine concentrations, and oxidative stress. Endothelium-dependent, flow-mediated dilation of the brachial artery measured by ultrasound, and coronary calcium volume measured by electron beam computed tomography (EBCT) will provide functional and structural measures of vascular integrity, respectively. The pathogenesis of atherosclerosis and inflammation have strong genetic components. We will examine the role of such genetic factors focusing initially on nitric oxide (NO), a mediator that affects both structural and functional vascular integrity, and test the hypothesis 3) that polymorphism of the endothelial nitric oxide synthase gene is associated with vascular damage in SLE. Of great interest are recent studies showing that HMG coenzyme-A reductase inhibitors (statin lipid lowering drugs) can reverse vascular damage, through both lipid lowering and lipid-independent mechanisms. We will examine the hypothesis 4) that vascular damage in SLE is reversible by treatment with a statin drug. The proposed studies will provide a basic understanding of the interrelationship between inflammation, oxidative stress, genetic polymorphism, and vascular damage, and will suggest strategies for reversing or preventing such damage in SLE and, potentially, other diseases.
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