The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus

Abstract

Patients with systemic lupus erythematosus have up to a 50-fold increased risk of developing atherosclerotic cardiovascular disease. Recent advances in the etiology of vascular damage in this disease stress the interplay of lupus-specific inflammatory factors with traditional cardiac risk factors, leading to increased endothelial damage. This review analyzes the putative role that immune dysregulation and lupus-specific factors may play in the pathogenesis of premature vascular damage in this disease. The potential role of various cytokines, in particular type I interferons, in the development of accelerated atherosclerosis is examined. Potential therapeutic targets are discussed.

Figure 1

Endothelial progenitor cells/circulating angiogenic cells from patients with systemic lupus erythematosus are unable to differentiate into mature endothelial cells in culture. Photomicrographs of primary blood mononuclear cells from a healthy control (left) and a patient with systemic lupus erythematosus (right) after 2 weeks of culture in proangiogenic media on fibronectin-coated plates. Cells were imaged via inverted phase microscopy at a total magnification of 100×. Photomicrographs by Seth G Thacker.

Figure 2

The interplay of various inflammatory mediators increases vascular damage and plaque formation in systemic lupus erythematosus. IFN-α contributes to endothelial dysfunction and decreased repair of endothelial damage by decreasing numbers and function of endothelial progenitor cells (EPCs) and circulating angiogenic cells (CACs). In addition to synthesizing type I IFNs, low density granulocytes (LDGs) present in systemic lupus erythematosus patients are directly toxic to the endothelium. Altered lipid profiles secondary to abnormal chylomicron processing, increased pro-inflammatory high density lipoprotein (pi-HDL) and increased oxidized low density lipoprotein (ox-LDL) also promote atherosclerosis development. The abnormal redox environment in systemic lupus erythematosus also promotes endothelial dysfunction and modulates lipid profiles. Antibodies to lipoproteins or endothelial targets may also contribute to vascular damage. Cytokines such as TNF-α, IL-17 and IFN-γ may also have pro-atherogenic effects on blood vessels. The combination of some or all of these factors in an individual patient results in endothelial dysfunction, increased plaque burden and an increased risk of cardiovascular events. IC, immune complex; PDC, plasmacytoid dendritic cell; RNS, reactive nitrogen species; ROS, reactive oxygen species.