Metabolic syndrome: the danger signal in atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by infiltration of blood vessels by lipids and leukocytes. There is a growing body of evidence that among risk factors that promote atherosclerosis, the metabolic syndrome is a powerful and prevalent predictor of cardiovascular events. The systemic inflammatory process associated with the metabolic syndrome has numerous deleterious effects that promote plaque activation, which is responsible for clinical events. Interactions between the innate immune system with lipid-derived products seem to play a major role in the pathophysiology of atherosclerosis in relation with the metabolic syndrome. The multiple links among adipose tissue, the vascular wall, and the immune system are the topics of this review, which examines the roles of oxidized low-density lipoprotein, inflammatory cytokines, and adipokines in triggering and perpetuating a danger signal response that promotes the development of atherosclerosis. Furthermore, therapeutic options that specifically target the metabolic syndrome components are reviewed in light of recent developments.

Figure 1

Peroxisome proliferators-activated receptor (PPAR-γ) is a member of nuclear receptor superfamily that regulates in macrophages numerous functions that have important impact on the development of atherosclerosis. It up-regulates the expression of the CD-36 scavenger receptor and has therefore a potential to increase atherosclerosis (in red). On the other hand, PPAR-γ reduces the expression of pro-inflammatory mediators and increases LXR expression, a nuclear receptor that control the level of adenosine triphosphate (ATP)-binding cassette protein-1 (ABCA-1), which mediates the apo-A1 mediated reverse cholesterol transport (green). Thus, the balance of PPAR-γ activity indicates that an antiatherosclerotic effect (green) might be superior to the pro-atherosclerotic effect (red), explaining the beneficial effect of the thiazolidinediones (TZDs). Abbreviations: apo-A1, apolipoprotein A1; CCR2, CC-chemokine receptor 2; IL-1β, interleukin 1β; IL-6, interleukin 6; LXRα, liver X nuclear receptor; ox-LDL, oxidized low-density lipoprotein; TNF-α, tumor necrosis factor-α.

Figure 2

The metabolic syndrome is characterized by visceral obesity and its attendant metabolic perturbations that have numerous pro-atherosclerotic effects on the arterial wall. Production of small dense LDL particles and decrease HDL levels increase vascular infiltration by lipids and the production of oxidized LDL (ox-LDL). Ox-LDL delivers a danger signal to the macrophages and the production of foam cells producing cytokines and growth factors that will promote the development of atherosclerosis. In addition, elevated blood levels of cytokines and of adipokines contribute to increase the inflammatory reaction. Abbreviations: apo A1, apolipoprotein A1; apo B, apolipoprotein B; AT1-R, angiotensin 1 receptor; CRP, C-reactive protein; HDL-C, high-density lipoproteincholesterol; HSPs, heat shock proteins; IL-1β, interleukin 1β; IL-6, interleukin 6; INF-γ, interferon-γ LDL-C, low-density lipoprotein-cholesterol; MCP-1, monocyte chemotactic protein 1; MMPs, matrix metalloproteinases; TNF-α, tumor necrosis factor-α.

Figure 3

Visceral obesity is a key component of the metabolic syndrome. Free fatty acids (FFA) and interleukin 6 (IL-6) produced by abdominal fat cells are drained up to the liver via the portal vein and contribute to the production of very low-density lipoprotein (VLDL) and C-reactive protein (CRP). VLDL through exchange of cholesteryl esters and triglycerides (TGs) contribute to the generation of highly atherogenic small and dense low-density lipoprotein (LDL) particles that are easily transformed to oxidized products that deliver a danger signal. In addition, abdominal fat cells produce resistin and leptins that deliver a danger signal, whereas lower levels of adiponectin contribute to amplify the pro-atherogenic signal through the loss of its protective effects. Abbreviations: ox, oxidized; Th-1, T helper 1.