Among the more interesting are the apoE-/- mouse with mutations in Fas or FasL (lpr for Fas; gld for FasL). accumulation of lipids in the vessel wall. Recently, however, it has been realized that inflammation plays a role not only in the development of the atherosclerotic lesion, but also in the acute rupture of plaques that occurs during acute myocardial ischemic events [4, 5]. As in the pathogenesis of SLE itself, the interplay of multiple inflammatory mediators, including leukocytes, cytokines, chemokines, adhesion molecules, complement, as well asantibodies promotes damage of endothelium and formation of the plaques and vascular easy muscle hypertrophy that narrow arteries in atherosclerosis [6]. The Role of Inflammation in the Pathogenesis of Atherosclerosis The Recruitment of Inflammatory Cells to the Arterial Wall Atherosclerotic lesions begin with the recruitment of inflammatory cells such as monocytes and T-cells to the endothelial wall. First, the vascular endothelial cells are stimulated to express leukocyte adhesion molecules, including E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) [6]. These cell-surface proteins are upregulated during periods of inflammation. For example, the expression of adhesion molecules can be induced by pro-inflammatory cytokines such as Tumor Necrosis Factor- (TNF-) and Interleukin-1 (IL-1), which upregulate leukocyte adhesion molecules in an NF-B dependent process Begacestat (GSI-953) [6]. VCAM-1 is also induced when endothelial cells are exposed to other inflammatory signals, such as the lipopolysaccharides of Gram-negative bacteria, lysophosphatidylcholine (LPC), and oxidized phospholipids such as oxidized low density lipoprotein (OxLDL) [7, 8]. High density lipoproteins (HDL) inhibit the expression of adhesion molecules [9, 10]. The importance of these adhesion molecules in the development of atherosclerosis is usually highlighted by the fact that atherosclerosis-prone apoE deficient mice who are also deficient in E-selectin develop fewer plaque lesions [11]. Also, soluble levels of VCAM-1 can be detected in the systemic circulation, and elevated levels of this adhesion molecule have been found in humans with coronary artery disease [12, 13]. In one cross Rabbit Polyclonal to ATP5D sectional carotid ultrasound study of SLE patients, however, neither levels of soluble VCAM nor ICAM were significantly associated with carotid plaque [2] After leukocytes adhere to the cell surface, they migrate through the endothelium and into the intima [6]. This transmigration is usually influenced by several factors; first, several chemotactic proteins such as monocyte chemotactic protein-1 (MCP-1) are produced by the endothelial and easy cell layers Begacestat (GSI-953) [14]. The expression of MCP-1 in easy muscle cells and endothelial cells can be upregulated by cytokines such as TNF- and IL-1 and by OxLDL [14, 15]. Conversely, normal HDL inhibit the expression Begacestat (GSI-953) of MCP-1 [16]. The importance of MCP-1 in the development of the atherosclerotic plaque is usually emphasized by the fact that elevated circulating levels of MCP-1 are positively related to increased carotid artery IMT in humans [17]. Also, in LDLR-/- mice, knockout of MCP-1 reduces the atherosclerosis induced by high excess fat diets [18]. Low Density Lipoproteins and the Development of Foam Cells Next, low density lipoproteins (LDL) are transported into artery walls, where they become trapped and bound in the extracellular matrix of the subendothelial space [19]. These trapped LDL are then seeded with reactive oxygen species (ROS) produced by nearby artery wall cells, resulting in the formation of pro-inflammatory oxidized LDL [19]. When endothelial cells [20] are exposed to these pro-inflammatory OxLDL, they release cytokines such as MCP-1, M-CSF, and GRO, resulting in.