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. 2013 Mar 6;4(2):176–190. doi: 10.3945/an.112.003210

Figure 3.

Figure 3

Signaling pathway for zinc prevention of atherosclerosis in monocytes/macrophages and vascular endothelial cells: a proposed hypothesis. Reactive oxygen species (ROS) induced by many stimuli modifies LDL into oxidized LDL (oxLDL) in macrophages and vascular endothelial cells. oxLDL or ROS can activate the apoptotic pathway via activation of proapoptotic enzymes and the nuclear transcription factor κB (NF-κB) pathway via NF-κB inducible kinase (NIK) activation, which eventually results in the development and progression of atherosclerosis. Zinc might have an atheroprotective function by the following mechanisms: 1) inhibition of ROS generation via metallothionein (MT), superoxide dismutase (SOD), and inhibition of NADPH oxidase and 2) downregulation of atherosclerotic cytokines/molecules such as inflammatory cytokines, adhesion molecules, inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), fibrinogen, and tissue factor (TF) through inhibition of NF-κB activation by A20-mediating TNF–receptor associated factor (TRAF) signaling and peroxisome proliferator–activated receptor α (PPAR-α)–mediating crosstalk signaling. The black arrows indicate upregulation; arrows with a broken line indicate downregulation or the inhibitory pathway. IKK, IκB kinase; MCP-1, macrophage chemoattractant protein 1; CRP, C-reactive protein; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1. Reproduced with permission from (46).