Atherosclerosis; cell biology and lipoproteins: lipid metabolism, eicosanoids, peroxisome proliferator activated receptors and the atherogenic process.

摘要

Arachidonic acid (20:4 n-6) is a 20-carbon unsaturated fatty acid, found in mammalian tissues. Arachidonic acid can participate in numerous events as an intracellular regulator or can be converted to a range of oxygenated metabolites (eicosanoids) which have diverse biological actions on various systems of the body, both homeostatic and pathophysiological, being involved in inflammatory and antiinflammatory processes. There are three major routes of metabolism of arachidonic acid (all cis-5, 8, 11, 14 eicosatetraenoic acid). Arachidonic acid can be oxygenated by either cyclooxygenases to generate prostanoids,by lipoxygenases to generate leukotrienes and lipoxinsor by cytochrome P450 monooxygenases (CYPs) to generate epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoicacids (HETEs) . Eicosanoids are produced in a tissue and cell-specific manner. CYP-derived eicosanoids which participate in regulation of vascular smooth muscle tone are produced in the endothelium.They are synthesized predominantly by epoxygenasesof the CYP2C and CYP2J family which form the regio and stereospecific epoxides 5, 6, 8, 9, 11,12, and 14,15-EETs and the arachidonic acid omega/omega-1-hydroxylases of the CYP4A family which form 20-HETE. Functionally, EETs can modulate cell proliferation, cell migration, angiogenesis and blood flow in the peripheral vasculature.Levels of free EETS appear to be strictly controlled by factors affecting GYP. For example GYP2C levels are upregulated by physiological stimuli such as hypoxia and stretch (fluid shear stress and cyclic stretch) and CYP activity is modulated posttranslationally by phosphorylation,subcellular localization, proteosomal degradation and nitric oxide-dependent modification of the heme moiety. Free EET levels are further modulated byenzyme action. EETs are hydrated by soluble epoxide hydrolase (sEH) contained in the cytosol to the corresponding dihydroxyeicosatrienoic acid or degraded by (3 oxidation, The exception is 5,6-EET which is metabolized to 5,6-epoxy prostaglandin 1 by cyclooxygenase-2 .