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Figure 2. Pathways for uric acid-mediated endothelial (A) and vascular smooth muscle cell (B) damage. In endothelial cells, high uric acid levels stimulate the RAGE signaling pathway and activates NF-κB. This process conduces to the extracellular release of HMGB1 in endothelial cells, and its interaction with RAGE due to its high affinity contributes to the amplification of the inflammatory response, finally inducing endothelial dysfunction. In addition, intracellular uric acid causes P38 and extracellular signal-regulated kinase (ERK) 42/44 MAPK phosphorylation, increasing aldose reductase expression and inducing NOX4 over expression and ROS production. Moreover, uric acid contributes to a pro-inflammatory state, mediated by TLR-4 with NOX4 up-regulation, NLRP3 activation and interleukin production, promoting cellular switching and apoptosis. The ROS produced by xanthine oxidase are an important messenger inducing inflammation and signal transduction, such as mitochondrial dysfunction, leading to apoptosis, increase in proinflammatory cytokines and phenotype transition (A). In VSMCs, uric acid induces proinflammatory cytokine production, apoptosis, and endothelial-mesenchymal transition by several pathways. Uric acid enters the vascular smooth muscle cell where it alters intracellular redox, activates mitogen activated protein kinases (Erk1/2 and p38), COX-2, and nuclear transcription factors (NFκB and AP-1), leading to synthesis of cytokines and PDGF, as well as proliferation and phenotype transition of these cells. The ROS increase and NLP3 activation have similar effects as in endothelial cells. Finally, it has been demonstrated UA-mediated up-regulation of macrophage MIF protein, a cytokine playing inflammatory response induced in VSMCs by oxidized low-density lipoproteins and Ang II during atherogenesis. The two pink boxes summarize the UA-mediated effects on the two cell types, and their interaction brings up an interesting and new aspect of the research, as described in the text (B). AGT: Angiotensinogen; AP-1: activator protein-1; COX-2: inducible cyclo-oxygenase; HMGB1: high-mobility group protein-1; IL: interleukin; MAPK: mitogen-activated protein kinase; MIF: migration inhibitory factor; NLRP3: Nod-like receptor pyrin domain-containing protein 3; NOX4: NADPH oxidase 4; ROS: reactive oxygen species; OAT: organic anion transporter; RAGE: receptor for advanced glycation end products; TLR4: toll-like receptor 4; VSMC: vascular smooth muscle cell.