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Friday, September 18, 2015

Imbalance between oxLDL and nitric oxide - main drivers of heart disease and ageing

“longevity is a vascular question. A man is as old as his arteries”
-- William Osler, 1892

Oxidized LDL and NO synthesis—Biomarkers of endothelial dysfunction and ageing

LDLs as main blood cholesterol carriers, containing relevant amount of polyunsaturated fatty acids (PUFAs) – major substrate for lipid peroxidation, are among various molecular targets the most affected by the oxidative stress associated with metabolic imbalance (hyperlipidemia, hyperglycemia, insulin resistance). Therefore, the oxidative modification hypothesis of atherosclerosis recognizes the crucial role of oxLDL as a byproduct of LDLs exposure to ROS (Steinberg and Witzum, 2010).

OxLDL promotes endothelial dysfunction and contributes to the atherosclerotic plaque formation, progression and destabilization, by several mechanisms described in numerous recent review articles (Maiolino et al., 2013b; Pirillo et al., 2013; Xu et al., 2013; Le, 2015): (1) chemotactic recruitment, activation, and proliferation of monocytes/macrophages in the arterial wall, through the induction of the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular-cell adhesion molecule-1 (VCAM-1), thus stimulating their binding to endothelial cells; (2) its identification and rapid uptake by macrophages, followed by foam cells formation; (3) stimulation of smooth muscle cells (SMCs) migration and proliferation in the tunica intima, following the increase of the expression of growth factors, such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor (FGF) by endothelial cells and macrophages. Subsequently, oxLDL stimulate collagen production by SMCs and increase secretion of matrix metalloproteinases 1 and 9 (MPP-1 and MPP-9) inducing SMCs apoptosis; (4) cytotoxicity exerted mainly on the endothelial cells, which promote their apoptosis and the release in the subendothelial space of lipids and lysosomal enzymes; (5) stimulation of platelet adhesion and aggregation by decreasing endothelial production of nitric oxide, increasing prostacyclin production; (6) blockage of coronary artery relaxation (vasoconstriction) by downregulating eNOS expression, by inhibiting NO and increasing endothelin production. The above evidences explain the pro-inflammatory, pro-oxidant, pro-thrombotic, and vasoconstrictor actions of oxLDL, accounting for its global pro-atherogenic effect on vascular endothelium.


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