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. 2015 Mar 3;9:65. doi: 10.3389/fncel.2015.00065

Figure 2.

Figure 2

Cellular and histological effects of amyloid peptide β on the endothelium. Direct stimulation of the receptor for advanced glycation end products (RAGE) stimulates NADPH oxidases (NOXs), intracellular calcium increase and c-Jun N-terminal kinases (JNKs). The stimulation of NOXs and generation of reactive oxygen species (ROS) induce the activation of hypoxia-induced factor 1 (HIF) and NF-E2-related Factor 2 (Nrf2). Together with the activation of JNKs, the activity of these transcription factors leads to upregulation of pro-inflammatory genes, including cyclooxygenase 2 (COX2), metalloproteases (MMPs), interleukins 1β/6/8 (IL1β/6/8), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor α (TNF α) and transforming growth factor beta (TGF-β). Additional effect of ROS increase are the reduction of nitric oxide (NO) bioavailability, which leads to pro-thrombotic endothelial cell phenotype, and apoptosis. The intracellular calcium increase leads to intimal loosening via zona occludens protein 1 (ZO-1). The accumulation of thrombin in the amyloid plaques further facilitates endothelial inflammation via stimulation of the protease-activated receptors (PARs).