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: 8.13). 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
  • [Show abstract] [Hide abstract]
    ABSTRACT: The synthesis of oxygenated eicosanoids is the result of the coordinated action of several enzymatic activities, from phospholipase A2 that releases the polyunsaturated fatty acids from membrane phospholipids, to primary oxidative enzymes, such as cyclooxygenases and lipoxygenases, to isomerases, synthases and hydrolases that carry out the final synthesis of the biologically active metabolites. Cells possessing the entire enzymatic machinery have been studied as sources of bioactive eicosanoids, but early on evidence proved that biosynthetic intermediates, albeit unstable, could move from one cell type to another. The biosynthesis of bioactive compounds cold therefore be the result of a coordinated effort by multiple cell types that has been named transcellular biosynthesis of the eicosanoids. In several cases cells not capable of carrying out the complete biosynthetic process, due to the lack of key enzymes, have been shown to efficiently contribute to the final production of prostaglandins, leukotrienes and lipoxins. We will review in vitro studies, complex functional models, and in vivo evidences of the transcellular biosynthesis of eicosanoids and the biological relevance of the metabolites resulting from this unique biosynthetic pathway. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 09/2014; · 4.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The endogenous ligands for the leukotriene, lipoxin and oxoeicosanoid receptors are bioactive products produced by the action of the lipoxygenase family of enzymes. The leukotriene (LT) receptors are either activated by LTB4 (BLT1 and BLT2 ) or cysteinyl-LTs (CysLT1 and CysLT2 ), whereas oxoeicosanoids exert their action through the OXE receptor. In contrast to these pro-inflammatory mediators, the lipoxin (LX) A4 transduces responses associated with the resolution of inflammation through the receptor FPR2/ALX (ALX/FPR2). The aim of the present review is to give a state of the field on these receptors, with focus on recent important findings. For example, BLT1 receptor signaling in cancer and the dual role of the BLT2 receptor in pro- and anti-inflammation have added more complexity to lipid mediator signaling. Furthermore, a cross-talk between the CysLT and P2Y receptor systems has been described, and also the presence of novel receptors for cysteinyl-LTs, such as GPR17 and GPR99. Finally, lipoxygenase metabolites derived from omega-3 essential polyunsaturated referred to as resolvins activate the receptors GPR32 and ChemR23. In conclusion, the receptors for the lipoxygenase products make up a sophisticated and tightly controlled system of endogenous pro- and anti-inflammatory signaling in physiology and pathology.
    British Journal of Pharmacology 03/2014; · 5.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (IH)-induced inflammation. Cyclooxygenase (COX)-formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (CBF), but their role in blood pressure and CBF responses to IH is unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses to IH. Twelve healthy, male participants underwent three, 6-hour IH exposures. For 4 days before each IH exposure, participants ingested a placebo, indomethacin (nonselective COX inhibitor), or Celebrex(®) (selective COX-2 inhibitor) in a double-blind, randomized, crossover study design. Pre- and post-IH blood pressure, CBF, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreated OSA patients (n=33). Nonselective COX inhibition increased pre-IH blood pressure (P≤0.04) and decreased pre-IH CBF (P=0.04) while neither physiological variable was affected by COX-2 inhibition (P≥0.90). Post-IH, MAP was elevated (P≤0.05) and CBF was unchanged with placebo and nonselective COX inhibition. Selective COX-2 inhibition abrogated the IH-induced MAP increase (P=0.19), but resulted in lower post-IH CBF (P=0.01). Prostanoids were unaffected by IH, except prostaglandin E2 was elevated with the placebo (P=0.02). Finally, OSA patients had elevated blood pressure (P≤0.4) and COX-1 formed thromboxane A2 concentrations (P=0.02). COX-2 and COX-1 have divergent roles in modulating vascular responses to acute and chronic IH. Moreover, COX-1 inhibition may mitigate cardiovascular and cerebrovascular morbidity in OSA. Unique identifier: NCT01280006.
    Journal of the American Heart Association. 04/2014; 3(3):e000875.


Available from
May 28, 2014