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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    • "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.
    Journal of Pharmaceutical and Biomedical Analysis 06/2015; 110:12-19. DOI:10.1016/j.jpba.2015.02.041 · 2.98 Impact Factor
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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. Atherosclerotic plaques and AAA specimens were selected from two independent databases for LTB4 measurements. Plaques were isolated during carotid endarterectomy from asymptomatic (n = 58) or symptomatic (n = 317) patients, classified prior to surgery. LTB4 levels were measured without prior lipid extraction and levels were corrected for protein content. LTB4 levels were related to plaque phenotype, baseline patient characteristics and clinical outcome within three years following surgery. Seven non-diseased mammary artery specimens served as controls. AAA specimens were isolated during open repair, classified as elective (n = 189), symptomatic (n = 29) or ruptured (n = 23). LTB4 levels were measured similar to the plaque measurements and were related to tissue characteristics, baseline patient characteristics and clinical outcome. Twenty-six non-diseased aortic specimens served as controls. LTB4 levels corrected for protein content were not significantly associated with histological characteristics specific for vulnerable plaques or inflammatory AAA as well as clinical presentation. Moreover, it could not predict secondary manifestations independently investigated in both databases. However, LTB4 levels were significantly lower in controls compared to plaque (p = 0.025) or AAA (p = 0.017). LTB4 levels were not associated with a vulnerable plaque phenotype or inflammatory AAA or clinical presentation. This study does not provide supportive evidence for a role of LTB4 in atherosclerotic plaque destabilization or AAA expansion. However, these data should be interpreted with care, since LTB4 measurements were performed without prior lipid extractions.
    PLoS ONE 01/2014; 9(1):e86522. DOI:10.1371/journal.pone.0086522 · 3.23 Impact Factor
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    • "Taken together, these findings open up for a role of thromboxane in atherosclerosis and vascular injury, which goes beyond platelet aggregation. In support of the latter notion, either genetic or pharmacological targeting of the TP receptor reduces atherosclerosis in hyperlipemic mice [4] [5] [6] [7] [8] [9], an effect which is not observed with aspirin treatment [10]. Thromboxane A 2 and isoprostanes can stimulate endothelial TP receptors and increase the expression of proinflammatory markers such as ICAM-1 and VCAM-1 [6]. "
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    ABSTRACT: The prothrombotic mediator thromboxane A2 is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-Keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy.
    Biochemical and Biophysical Research Communications 10/2013; 441(2). DOI:10.1016/j.bbrc.2013.10.078 · 2.30 Impact Factor
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