Atherosclerosis is a chronic inflammatory disease in the subendothelial layer of large- and medium-sized arteries. It is characterized by the formation of atherosclerotic plaques consisting of a necrotic core, calcified regions, accumulated modified lipids, vascular smooth muscle cells (VSMCs), endothelial cells, leukocytes, and foam cells. Chronic endothelial injury, due to hypertension, hemodynamic disturbances, hypercholesterolemia, and oxidative stress results in endothelial dysfunction, increased permeability, LDL oxidation and an inflammatory response associated with increased expression of adhesion molecules and chemokines that participate in platelet aggregation, lymphocyte and monocyte adhesion and infiltration, and macrophage activation.Reactive oxygen species (ROS) are key mediators of signalling pathways that underlie vascular inflammation in atherosclerosis - from lesion progression to plaque rupture. Changes in the oxidative milieu due to increased ROS bioavailability regulate the activity of many signalling modulators through post-translational modification, including inactivation of protein-tyrosine phosphatases (PTPs) through cysteine (Cys) oxidation. Protein tyrosine phosphatase 1B (PTP1B) regulates downstream tyrosine kinase receptor-mediated responses and influences endothelial function as well as mitogen-activated protein kinases (MAPK) activity and angiogenesis-dependent on VEGFR2 signalling.Considering that atherosclerosis is a chronic inflammatory disease regulated by sensitive redox pathways and PTP activity is associated with vascular dysfunction, this project proposes to determine whether changes in the redox environment to an oxidative state promote PTP oxidation, leading to proinflammatory events, endothelial and VSMC dysfunction and consequently to a pro-atherosclerotic milieu.
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