The endothelium is the primary target for biochemical or mechanical injuries caused by the putative risk factors of atherosclerosis. Endothelial dysfunction represents the ultimate link between atherosclerotic risk factors that promote atherosclerosis. HDL-C is thought to exert at least some parts of its antiatherogenic facilities via stimulating endothelial NO production, nearby inhibiting oxidative stress and inflammation. HDL-C is capable of opposing LDL’s inductive effects and avoiding the ox-LDL’s inhibition of eNOS. Paraoxonase 1 (PON1) is an HDL-associated enzyme esterase which appears to contribute to the antioxidant and antiatherosclerotic capabilities of HDL-C. “Healthy HDL,” namely the particle that contains the active Paraoxonase 1, has the power to suppress the formation of oxidized lipids. “Dysfunctional HDL,” on the contrary, has reduced Paraoxonase 1 enzyme activity and not only fails in its mission but also potentially leads to greater formation of oxidized lipids/lipoproteins to cause endothelial dysfunction. The association of HDL-C PON1 and endothelial dysfunction depends largely on the molecules with exact damaging effect on NO synthase coupling. Loss of nitric oxide bioavailability has a pivotal role in endothelial dysfunction preceding the appearance of atherosclerosis. Analyses of HDL-C and Paraoxonase1 would be more important in the diagnosis and treatment of atherosclerosis in the very near future. 1. Introduction Lipoproteins and their alterations are very frequently linked with increased risk of developing atherosclerotic disease. Recent studies introduce a function-based approach on evaluation of both the lipoprotein particles and the ultimate target: the endothelium. Considering particularly the high-density lipoprotein-cholesterol (HDL-C), there are two different definitions: HDL-C quantity, which means the circulating plasma levels of the particle; and HDL-C quality, which means the atheroprotective properties of HDL-C. Bare measurements of plasma concentrations, while shown to be epidemiologically predictive of atherosclerotic cardiovascular events in large populations, are insufficient to capture the functional variations in HDL-C particles and the risk of atherosclerotic disease associated with it. Functionality hypothesis suggests that measurement of HDL-C levels has no major relationship with how the HDL-C concentrations are being dynamically remodeled or the state of HDL-C capability [1]. The goal of this paper is to summarize the recent data on HDL-C functionality and to make connections between separate findings
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