ReviewProstanoid and isoprostanoid pathways in atherogenesis
Introduction
The term “atherosclerosis” was first introduced to describe the association of vessel stiffening and fatty acid degeneration [1]. Typically, this process affects medium and large-sized arteries and is characterized by intramural thickening of the sub-intimal space protruding into the vessel lumen. Atherosclerosis is the culprit behind coronary artery disease, cerebral vascular disease, and peripheral vascular disease, and for this reason, is considered the most common cause of death of the 21st century in western societies [2]. Atherosclerosis is a chronic and progressive vascular disease, its pathogenesis is complex and multiple contributing mechanisms have been identified including endothelial dysfunction, dyslipidemia, hypercoagulability, just to mention a few [3], [4], [5], [6], [7], [8]. All of these factors influence the disease onset and progression by modulating the interaction among components of the blood as well as the arterial wall, which finally results in a chronic state of vascular oxidative stress and inflammation [9].
Prostanoids, isoprostanoids and their vascular receptors play a central role in modulating inflammatory processes, whereby having a direct impact on the vascular phenotype. This influence is mediated through a variety of mechanisms and processes including platelet reactivity and aggregability, leukocyte-endothelial cell interactions, endothelium responses, which ultimately are all key events in the local inflammatory response of the vasculature. Recent evidence has clearly indicated that not only all of these bioactive lipid mediators and their receptors are altered, but that also they play a functional role in atherogenesis [10]. The goal of this article is to review our current knowledge regarding the biological roles that prostanoids, isoprostanoids and their pathways play in atherosclerosis. This information could provide a mechanistic framework to understand the clinical benefit of old and newer therapeutic approaches targeting these mediators, and to develop therapeutic strategies aimed at preventing or reducing the mortality resulting from atherosclerosis.
Section snippets
Prostanoids
Prostanoids are members of a large family of lipid mediators called also eicosanoids. They are metabolic derivatives of arachidonic acid (AA), and the various eicosanoid sub-classes are generated by distinct metabolic pathways. AA undergoes oxidation by one of three types of enzyme: lipoxygenases (LOX), to form leukotrienes and lipoxins; cyclooxygenases (COX), to form prostanoids (i.e. prostaglandins and thromboxanes); and cytochrome P-450 monooxygenases, to form epoxides [10] (Fig. 1).
This
Isoprostanoids
Isoprostanoids are an emerging class of bioactive lipids also products of the AA oxidative metabolism formed not via the classical COX-dependent pathways(s), but a free radical-mediated mechanism [60] (Fig. 4). From a chemical point of view they represent a large family of prostaglandin isomers. However, by contrast with the classic prostaglandins, which are formed from free AA, they are formed in situ from the fatty acid backbone esterified in membrane phospholipids, where they are also
The TP receptor system as the biologic link between prostanoids and isoprostanoids in atherogenesis
We have widely discussed the notion that prostanoids manifest important biologic activities whereby modulating the proatherogenic vascular phenotype of atherogenesis. As discussed in the previous paragraph, isoprostanoids also have several biological effects which support the novel idea that they function as mediators of the biological cellular response to oxidative stress events within the vasculature.
Human and experimental atherosclerosis is characterized by an altered biosynthesis of both
Conclusions and future perspectives
Atherosclerosis is a chronic vascular disease resulting from a complex interplay of exogenous and endogenous factors. It is well accepted that one hallmark feature of the disease is the presence of a chronic inflammation within the vasculature. Prostanoids and isoprostanoids play a central role in inflammation and have been implicated in the pathogenesis of atherosclerosis.
Prostanoids and the enzymes responsible for their formation, COX-1 and COX-2, are both increased in atherogenesis,
Acknowledgments
The work from the author's laboratory described in the present article was supported by grants from the National Institute of Health, the American Heart Association, and the American Federation for Aging Research.
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