Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy.
Medicinal Research Reviews (Impact Factor: 8.43). 03/2013; 33(2). DOI: 10.1002/med.21251
Source: PubMed


Eicosanoids are biologically active lipids in both physiologic and pathophysiologic situations. These mediators rapidly generate at sites of inflammation and act through specific receptors that following the generation of a signal transduction cascade, lead to coordinated cellular responses to specific stimuli. Prostanoids, that is, prostaglandins and thromboxane A(2) , are active products of the cyclooxygenase pathway, while leukotrienes and lipoxins derive from the lipoxygenase pathway. In addition, a complex family of prostaglandin isomers called isoprostanes is derived as free-radical products of oxidative metabolism. While there is a wide consensus on the importance of the balance between proaggregating (thromboxane A(2) ) and antiaggregating (prostacyclin) cyclooxygenase products in cardiovascular homeostasis, an increasing body of evidence suggests a key role also for other eicosanoids generated by lipoxygenases, epoxygenases, and nonenzymatic pathways in cardiovascular diseases. This intricate network of lipid mediators is unique considering that from a single precursor, arachidonic acid, may derive an array of bioproducts that interact within each other synergizing or, more often, behaving as functional antagonists.

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Available from: G.Enrico Rovati
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    • "The latter compounds are further metabolized to dihydroxyeicosatrienoic acids (DHTs) [3]. These lipid-derived eicosanoids are involved in physiological processes through intracellular signaling and are implicated in pathophysiology of various disease states and inflammatory conditions such as hypertension, renal disorder, atherosclerosis, stroke, diabetes, obesity and cancer [4]. Ample of recent preclinical and epidemiologic data suggest that modulation of eicosanoids metabolism may be a feasible clinical therapeutic strategy for the management of different pathological disorder and in particular cardiovascular disease [2]. "
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    ABSTRACT: Eicosanoids are biologically active lipid-derived oxidative metabolites of arachidonic acid. We, herein, present an improved sensitive, selective and robust high performance liquid chromatography (HPLC)- fluorescence assay for simultaneous quantification of eicosanoids in human plasma and rat tissues. Aliquots of 200 L of plasma or 30 mg of heart or kidney tissues were spiked with 16-hydroxydecanoic acid as internal standard, and extracted with anhydrous acetonitrile using solid phase cartridges. The eluted samples were dried, reconstituted in anhydrous acetonitrile and labeled with 2-(2,3- naphthalimino)ethyl-trifluoromethanesulphonate in the presence of saturated potassium fluoride solutioninanhydrous acetonitrile and N,N-diiospropylethylamine as catalyst. Thederivatizedeicosanoids were extracted with anhydrous acetonitrile using solid phase cartridges. Chromatographic separation was achieved on a C18 reversed phase column using gradient mobile phase of 0.05% of formic acid:acetonitrile:water at 0.8 mL/min flow rate. The analytes were detected at excitation and emission wavelength of 260 and 396 nm, respectively. The assay was linear (r2 ≥ 0.98) in the concentration range of 0.01–2.5 g/mL. The intra-day and inter-day coefficients variation was less than 19.8%. Using this assay, we were able to quantify arachidonic acid metabolites simultaneously in human and rat biological samples.
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    • "There is experimental and clinical evidence supporting oxidative modification of LDL as an early and critical event in atherogenesis. Oxidation of LDL particles to atherogenic ones, on the one hand, generates high-uptake particles for macrophage and granulocyte scavenger receptor pathways leading to inappropriate accumulation of intracellular lipid deposits, and, on the other hand, generates a large panoply of lipid mediators promoting endothelial dysfunction and an inflammatory endothelial/subendothelial microenvironment[6,45,52]. The finding from earlier investigations that 2,3-diaryl indoles already show substantial antioxidative effects at pharmacologically relevant low levels prompted us to use consequently 1 M of each test compound in all experimental settings[33]. "
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    • "A mouse model for abdominal aortic aneurysm (AAA) formation revealed that BLT1 deficiency results in a lower incidence of AAA with a reduced tissue inflammation [11]. The aforementioned results suggest that leukotrienes, and LTB4 in particular, are actively involved in plaque instability and aneurysm formation [12]. Although ex vivo production of LTB4 has been associated with in human atherosclerotic plaques in the past [13], evidence in human studies supporting the role of LTB4 in both advanced atherosclerosis and AAA in secondary clinical outcome is scarce. "
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    ABSTRACT: Leukotriene B4 (LTB4) has been associated with the initiation and progression of atherosclerosis and abdominal aortic aneurysm (AAA) formation. However, associations of LTB4 levels with tissue characteristics and adverse clinical outcome of advanced atherosclerosis and AAA are scarcely studied. We hypothesized that LTB4 levels are associated with a vulnerable plaque phenotype and adverse clinical outcome. Furthermore, that LTB4 levels are associated with inflammatory AAA and adverse clinical outcome.
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