Article

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: 9.58). 03/2012; DOI: 10.1002/med.21251
Source: PubMed

ABSTRACT 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.

1 Bookmark
 · 
221 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Activation of thromboxane prostanoid (TP) receptor on platelets, monocytes/macrophages, endothelial cells (EC) and vascular smooth muscle cells (SMC) plays important roles in regulating platelet activation and vascular tone, and in the pathogenesis of thrombosis and vascular inflammation. Oxidative stress and vascular inflammation increase the formation of TP receptor agonists, which promote initiation and progression of atherogenesis and thrombosis. Furthermore, TP receptor activation promotes angiogenesis and vessel wall constriction. Besides thromboxane A2 (TXA2 ) and its endoperoxide precursors prostaglandin (PG)G2 and PGH2 , also isoprostanes and 20-hydroxyeicosatetraenoic acid (20-HETE) activate TP receptor as autocrine or paracrine ligands. These additional TP activators play a role in pathological conditions such as diabetes, obesity, and hypertension, and their biosynthesis is not inhibited by aspirin, at variance with that of TXA2 . The understanding of TP receptor function increased our current knowledge of the pathogenesis of atherosclerosis and thrombosis, highlighting the great impact that this receptor has in cardiovascular disorders. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 12/2013; · 6.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The thromboxane (Tx) A2 pathway is a major contributor to the amplification of the initial platelet activation process. TxA2 mediates its effect through the thromboxane prostanoid (TP) receptor that is expressed not only in platelets, but also in endothelial cells, macrophages, and monocytes, and thus contributes to the development of atherosclerotic lesions. The TxA2 pathway is therefore a major target in the treatment of cardiovascular disease. Aspirin-the most widely used antiplatelet drug-is very effective at inhibiting platelet-derived TxA2 synthesis. However, aspirin's effects can be overcome by several other soluble agonists such as isoprostanes, which are aspirin-insensitive ligands of the TP receptor that are preferentially produced in diabetes mellitus. Other drugs, with either inhibitory effects on Tx synthase or antagonist effects on TP, have been developed with the hope of providing a better, more complete inhibition of the TxA2 pathway.
    Journal of Cardiovascular Translational Research 12/2013; · 3.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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. · 3.53 Impact Factor

Full-text

View
88 Downloads
Available from
May 28, 2014