Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation
2013; Elsevier BV; Volume: 12; Issue: 2 Linguagem: Inglês
10.1111/jth.12472
ISSN1538-7933
AutoresValérie Capra, Magnus Bäck, Dominick J. Angiolillo, Marco Cattaneo, Kjell S. Sakaríassen,
Tópico(s)Nitric Oxide and Endothelin Effects
ResumoJournal of Thrombosis and HaemostasisVolume 12, Issue 2 p. 126-137 Review ArticleFree Access Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation V. Capra, V. Capra Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Milan, ItalySearch for more papers by this authorM. Bäck, M. Bäck Department of Medicine, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, SwedenSearch for more papers by this authorD. J. Angiolillo, D. J. Angiolillo Division of Cardiology, Department of Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, FL, USASearch for more papers by this authorM. Cattaneo, M. Cattaneo Medicina 3, Ospedale San Paolo – Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, ItalySearch for more papers by this authorK. S. Sakariassen, Corresponding Author K. S. Sakariassen KellSa s.a.s., Biella, Italy Correspondence: Kjell S. Sakariassen, KellSa s.a.s., Str. Campo e Zampe 12, I-13900 Biella, BI, Italy. Tel.: +39 015 25 24 359; fax: +39 015 25 27 615. E-mail: kjell.sakariassen@kellsa.comSearch for more papers by this author V. Capra, V. Capra Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Milan, ItalySearch for more papers by this authorM. Bäck, M. Bäck Department of Medicine, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, SwedenSearch for more papers by this authorD. J. Angiolillo, D. J. Angiolillo Division of Cardiology, Department of Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, FL, USASearch for more papers by this authorM. Cattaneo, M. Cattaneo Medicina 3, Ospedale San Paolo – Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, ItalySearch for more papers by this authorK. S. Sakariassen, Corresponding Author K. S. Sakariassen KellSa s.a.s., Biella, Italy Correspondence: Kjell S. Sakariassen, KellSa s.a.s., Str. Campo e Zampe 12, I-13900 Biella, BI, Italy. Tel.: +39 015 25 24 359; fax: +39 015 25 27 615. E-mail: kjell.sakariassen@kellsa.comSearch for more papers by this author First published: 03 December 2013 https://doi.org/10.1111/jth.12472Citations: 59 Manuscript handled by: J. Heemskerk Final Decision: P. H. Reitsma, 25 November 2013 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Summary The activation of thromboxane prostanoid (TP) receptor on platelets, monocytes/macrophages, endothelial cells, 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 and its endoperoxide precursors, prostaglandin G2 and H2, isoprostanes, and 20-hydroxyeicosatetraenoic acid also 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 thromboxane A2. 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. Introduction The thromboxane prostanoid (TP) receptor is a G protein–coupled receptor that is encoded in humans by the TBXA2R gene. It derives its name from its preferred endogenous agonist, thromboxane A2 (TXA2), which is the result of the conversion of arachidonic acid (AA) by cyclooxygenase (COX) and TXA2 synthase (TXS). TXA2 and its endoperoxide precursors prostaglandin (PG)G2 and PGH2 mediate a range of physiological and pathological responses in platelets, monocytes, macrophages, endothelial cells (ECs), and smooth muscle cells (SMCs), which all express TP receptor 1. TP mediates platelet activation, EC activation, vasoconstriction, and SMC proliferation, which are of particular relevance to cardiovascular diseases, in which TP receptor expression and TXA2 are elevated 2. The efficacy of platelet COX-1 inhibition of low-dose aspirin in the prevention of arterial thrombotic events provides evidence for the prominent role of platelet-derived TXA2 in cardiovascular disease 3. However, TXA2 has also important extraplatelet origins and TP receptor is activated also by other AA derivatives acting as autocrine or paracrine ligands, such as isoprostanes (e.g., 8-iso-PGF2α) and 20-hydroxyeicosatetraenoic acid (20-HETE). Isoprostanes are a complex family of prostaglandin isomers derived from nonenzymatic metabolism of AA following free radical attack of membrane phospholipids or low-density lipoprotein (LDL), while 20-HETE is synthesized by enzymes of the cytochrome P450 (CYP) 4A and 4F families (Fig. 1). Since aspirin does not inhibit the formation of these TP receptor agonists, the development of drugs targeting the TP receptor may be very important to further decrease the risk of arterial thrombosis in patients at risk. Figure 1Open in figure viewerPowerPoint Prostaglandin endoperoxide H synthase or cyclooxygenase (COX-1 and COX-2) converts arachidonic acid to the labile endoperoxide intermediate prostaglandins G2 and H2 (PGG2 and PGH2). PGH2 is then converted to thromboxane A2 (TXA2) by thromboxane synthase (TxS). Arachidonic acid is also metabolized by enzymes of the cytochrome P450 (CYP) 4A and 4F families to 20-hydroxyeicosatetraeonic acid (20-HETE) and is a substrate for non-enzymatic transformation to isoprostanes (Iso-P, e.g., 8-iso-PGF2α). All of them are agonists of the TP receptor (V-shaped) level. TP receptors are expressed on a variety of cells relevant to the cardiovascular pathobiology such as platelets, monocytes/macrophages, endothelial cells (EC) and vascular smooth muscle cells (SMC). Following activation, TP initiates signaling cascades that regulate EC activation, vascular SMC contraction, and platelet activation, which play a role in atherogenesis and/or thrombogenesis. Aspirin blocks COX-1, inhibiting the production of PGG2, PGH2 and TXA2, but not the production of 20-HETE and isoprostanes. Activation of the platelet TP receptor triggers platelet activation, secretion, and aggregation, which play important roles in the formation of both hemostatic plugs and pathological thrombi, particularly at high arterial wall shear rate 4. A normal response to TP receptor activation supports normal hemostasis. However, increased platelet TP receptor activation is frequently observed in platelet hyperreactivity states, particularly in patients with type 2 diabetes mellitus (DM) and acute coronary syndromes (ACS) 5, 6. This may be at least in part due to the increased formation of prostanoids and isoprostanes, which increases the risk of atherothrombosis and promotes vascular inflammation through TP receptor activation 7, 8. Vascular TP receptor activation promotes vasoconstriction, oxidative stress, and inflammation byvia various mechanisms and at various stages. Under normal conditions, TP receptor activated by endothelium-derived vasoactive factors participates to the control of vascular tone. Oxidative stress is initiated by the formation of cellular reactive oxygen species (ROS), and the inflammatory response is initiated by the adhesion and migration of monocytes into the vascular adventitia promoted by EC TP receptor activation 9, 10. Subsequently, adventitial SMC proliferation is stimulated/promoted by activation of the SMC TP receptors 11. The processes of oxidative stress and inflammation increase the production of prostanoids and isoprostanes 12-14. The resulting TP receptor activation promotes vascular inflammatory processes and the initiation and development of vascular lesions that are the first triggers for atherosclerosis. In addition, SMC TP receptor activation triggers vasoconstriction, increasing the arterial blood pressure, which is one of the major risk factors for atherothrombosis. TP receptor activation may play significant roles in several other clinical conditions 15, which will not be considered in the present review. The present review will focus on the multiple impacts of TP receptor activation on hemostasis, thrombosis, vascular oxidative stress and inflammation, and vascular tone 12-14. TP receptor signaling In humans, TP receptor exists in two isoforms, TPα and TPβ, which arise from alternative splicing after the seventh transmembrane domain and have different intracellular C-terminal intracytoplasmic edges 16, 17. The extracellular ligand binding and the transmembrane parts are identical, encompassing 328 amino acids, whereas the TPα and TPβ tails consist of 15 and 79 amino acids, respectively. Both TP receptor mRNA isoforms have been identified in several cells and tissues 1, but TPα is the dominant isoform translated in platelets 18 and vascular cells, whereas the TPβ isoform is present in ECs 19 and vascular SMCs 20. Prior investigations showed that the G proteins Gq and G12 are involved in platelet TP receptor signaling (Fig. 2) 17, 21. Stimulation of Gq activates phospholipase C-β ,resulting in accumulation of inositol 1,4,5-triphosphate (IP3), which leads to intraplatelet calcium mobilization, and diacylglycerol (DAG) formation, which causes activation of protein kinase C (PKC). In platelets, this signaling causes platelet shape change, aggregation, and secretion 17, 21. Platelet activation by TP is also dependent on stimulation of G13, which activates the Rho/Rho kinase pathway and subsequent myosin light chain phosphorylation 17, 21. Although it has been postulated that G12/13 activation is responsible for TP-mediated platelet shape change 22, 23, it is likely that both G12/13 and Gq are responsible for this platelet function. Platelets lacking both Gq and G13 are completely unresponsive to TXA2 24. Signaling through TP receptor in other cells may differ slightly from that in platelets 21. Figure 2Open in figure viewerPowerPoint Signaling pathways induced via thromboxane prostanoid (TP) receptor activation of Gq and G12/13 families of G proteins to induce platelet shape change, aggregation and secretion. Stimulation of Gq family proteins activates phospholipase C beta (PLCβ), which hydrolyzes membrane phosphatidylinositol-4,5-bisphosphate to release the second messengers inositol 1,4,5-triphosphate (IP3) and diacyl-glycerol (DAG). The resulting rapid and transient accumulation of IP3 leads to intra-platelet ionized calcium (Ca++) mobilization and DAG activates protein kinase C (PKC). Stimulation of G12 family proteins (G12 and G13) activates Rho-guanine nucleotide exchange factor (RhoGEF) and the RhoA/Rho associated protein kinase (ROCK) axis with subsequent myosin light chain (MLC) phosphorylation, contributing to platelet shape change. Abnormalities of the platelet TP receptor in patients with disorders of hemostasis Defects of the platelet TP receptor are associated with mild-moderate impairment of primary hemostasis, which is generally characterized by pathological mucocutaneous bleeding. The phenotype of patients with TP receptor defects is similar to that described in transgenic mice lacking TP receptor 25. Impaired platelet responses to TXA2 were described in 1981 in patients with bleeding disorders 26-28: their platelets displayed abnormal TXA2-dependent function, despite their ability to synthesize TXA2 normally. The hypothesized defect at the TP receptor level was confirmed by the finding that the stable TXA2 mimetic U46619 did not elicit normal platelet responses 28. A similar patient with mild bleeding disorder was subsequently described, whose platelets did not normally respond to the synthetic TXA2 mimetic STA2 29, due to defective coupling among TP receptor, G protein, and phospholipase C (PLC). This patient and a previously described one 30 had an Arg60-to-Leu mutation in the first cytoplasmic loop of both TPα and TPβ 31-33. The mutation was inherited as an autosomal dominant trait. A heterozygous Asp304-to-Asn substitution in TP receptor was recently described in a patient with impaired platelet response to U46619 and reduced platelet binding of the TP receptor antagonist [3H]SQ29548 34. Kamae et al. 35 described a severe defect of U46619-induced platelet aggregation and secretion in a 7-year-old girl and her father. Immunoblots showed that the TP receptor expression levels in their platelets were approximately 50% of controls, and nucleotide sequence analysis revealed that they were heterozygous for a novel mutation, c.167dupG, in the TP receptor cDNA. Expression studies in CHO cells indicated that the mutation was responsible for the expression defect in the TP receptor. Finally, Mumford et al. 36 described a patient with reduced platelet aggregation and secretion responses to TP receptor activators and a heterozygous Trp29-to-Cys substitution. Total TP receptor expression in patient's platelets was normal, but there was reduced maximum binding and reduced affinity of binding to the TP receptor antagonist [3H]SQ29548. Role of TP receptor activation in thrombosis: pharmacological and clinical effects of TP antagonists TXA2 is the major TP receptor agonist in platelets. However, other eicosanoids, including endoperoxides and isoprostanes, also play important roles in TP receptor activation 37. The key role of enhanced platelet reactivity in atherothrombosis underscores the importance of inhibiting crucial platelet signaling pathways 38. This is supported by the unequivocal clinical benefit, including reduction in mortality, of aspirin for secondary prevention of ischemic events through blockade of the platelet COX-1 enzyme 3. However, ischemic events continue to occur despite aspirin therapy. This may be in part attributed to persistent TP-dependent platelet activation despite aspirin therapy, which may occur because aspirin is unable to inhibit the formation of some TP receptor agonists 39. Therefore, it has been hypothesized that TP receptor antagonists might offer additive antithrombotic effects compared with aspirin. In a canine model, Fitzgerald et al. 40 showed that TP receptor antagonism caused disaggregation of platelet aggregates and relaxation of vascular smooth muscle contracted after coronary occlusion. Recently, Grad et al. 41 confirmed that suppression of the TP receptor pathway inhibits C-reactive protein (CRP)-induced platelet endothelial adhesion, aggregation, and thrombosis. Clinical studies have shown that patients with DM and those with ACS have increased propensity to generate TXA2 and other agonists able to activate TP receptors, whereas platelet-mediated vasodilatation is impaired 39. Moreover, in patients with DM hyperglycemia causes platelet ‘hyperreactivity’ and greater platelet turnover with new platelets released into the circulation twice faster than in normal subjects 42. Thus, enhanced TXA2-dependent platelet activation can contribute to the increased atherothrombotic risk of DM subjects 42, 43. Importantly, aspirin has lower COX-1–binding capacity in DM patients 43. Overall, these data identify DM patients as a population that might benefit from treatment with TP antagonists. Several TP receptor antagonists, including sulotroban, daltroban, ifetroban, ramatroban, linotroban, seratrodast, and terutroban, have been developed and studied in various phases of preclinical and clinical investigations (Table 1) 39. Among these, terutroban has been most broadly studied. Terutroban is an orally active TP receptor antagonist with reversible dose-dependent effect within 96 h 44. Using the Badimon blood perfusion chamber in a porcine model, 100 μg kg−1 day−1 of terutroban showed antithrombotic effects similar to the purinergic P2Y12 receptor antagonist clopidogrel 13. Antithrombotic effects of escalating doses of terutroban have also been shown in patients with peripheral artery disease (PAD) 45. Table 1. Drugs targeting thromboxane synthase and/or thromboxane receptor Drug Receptor Target Comments Daltroban (BM 13,505) TP A sulotroban derivative with partial agonism at TP receptor on vascular SM. Clinical development was discontinued in Phase I EV-077 TXS and TP In clinical Phase II development Ifetroban (BMS 180,291) TP A potent TP receptor antagonist derived from the endoperoxide PGH2. In clinical Phase II development for kidney failure Linotroban (HN-11500) TP A sulotroban derivative that was discontinued in clinical Phase II Ozagrel TXS Licensed in Japan (Endaravone®) for the treatment of thrombosis and asthma Picotamide TXS and TP Licensed in Italy (Plactidil®) for the treatment of arterial thrombosis and PAD Ramatroban TP and DP2 A sulotroban derivative, licensed in Japan (Baynas®) for the treatment of asthma and allergic rhinitis. Originally identified as a TP antagonist and later as a more potent DP2 antagonist Ridogrel TXS and TP Clinical development was discontinued. Potent TXS inhibitor but weak TP receptor antagonist Seratrodast TP Licensed in Japan (Bronica®) for the treatment of asthma Sulotroban (BM-13177) TP Clinical development was discontinued for evidence of partial agonism on vascular SM. Used as a prototype for the development of other compounds with improved TP antagonist activity Terbogrel TXS and TP Clinical development was discontinued in phase II due to induction of leg pain Terutroban (S-18886) TP Clinical development was discontinued during the Phase III Perform study, since terutroban was not more efficient than aspirin in prevention of strokes and heart attacks DM, diabetes mellitus; DP2, prostaglandin D2 subtype 2; PAD, peripheral artery disease; TXS, thromboxane synthase; TP, thromboxane prostanoid; SM, smooth muscle. Early-stage investigations have shown a potential role for terutroban in patients with prior ischemic stroke or carotid stenosis 46. However, these data were not supported by the phase III Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) study 47. This was a randomized, double-blind, parallel-group trial that enrolled about 20 000 subjects who had an ischemic stroke in the previous 3 months or a transient ischemic attack in the previous 8 days. Patients were randomized to 30 mg day−1 terutroban or 100 mg day−1 aspirin with a mean follow-up of 28 months. The study was stopped prematurely for futility and did not meet the predefined primary end point criteria for non-inferiority (a composite of fatal or non-fatal ischemic stroke, fatal or non-fatal myocardial infarction, or other vascular death). Further, there was an increase in minor bleedings with terutroban compared with aspirin, although there were no significant differences in other safety end points 47. Overall, based on these findings, the authors conclude that aspirin should be considered a better treatment option for secondary stroke prevention in view of its efficacy, tolerance, and cost. The antithrombotic activity of linotroban (HN-11500) was tested by using the Sakariassen human thrombosis blood perfusion chamber in healthy volunteers. A single oral dose of 100 μg linotroban was shown to be a potent inhibitor of formation of platelet-rich thrombi at a high arterial wall shear rate of 2.600 s−1 within 2 h following the administration 4. At a lower arterial wall shear rate of 650 s−1, linotroban administration resulted in loosely packed platelet-rich thrombi. However, linotroban did not go beyond phase II investigation. Other agents that possess inhibitory effects on both TXS and TP receptor, such as ridogrel, picotamide, terbogrel, and EV-077, represent another potential approach to achieve more comprehensive platelet inhibition (Table 1). These drugs, in addition to antagonize TP receptor, may have further antiplatelet effects deriving from the redirection of PG endoperoxide metabolism toward antiaggregatory PGI2 by EC. The Ridogrel vs. Aspirin Patency Trial (RAPT) study compared the efficacy and safety of ridogrel with that of aspirin as adjunctive therapy for patients with MI treated with thrombolysis 48. Although ridogrel was not superior to aspirin in enhancing the fibrinolytic efficacy of streptokinase, it was associated with a lower incidence of new thrombotic events (reinfarction, recurrent angina, ischemic stroke) without excess of serious bleeding complications 48. In line with this, the Drug evaluation in Atherosclerotic Vascular disease In Diabetics (DAVID) study, conducted in DM patients with PAD, showed that although picotamide compared with aspirin was not associated with any differences in the primary ischemic end point, it was associated with a significant reduction in cardiovascular mortality at 2 years with a favorable safety profile 49. Additionally, terbogrel showed enhanced platelet inhibition in vitro, which has been confirmed in a model of arterial thrombosis in rabbits 17. Although the clinical development of most of these compounds have been halted or not disclosed by makers of these agents, there have been recent investigations on a novel compound named EV-077. EV-077 is a potent dual TP receptor antagonist/TXS inhibitor and is still in early phase clinical investigation. In studies conducted in non-medicated healthy volunteers, significant inhibitory effects of escalating in vitro concentrations of EV-077, even when compared with aspirin, on platelet aggregation in platelet-rich plasma and whole blood were observed 50, 51. Moreover, Sakariassen et al. 37 evaluated the in vitro effects of EV-077 in patients with DM and stable coronary artery disease (CAD) on aspirin therapy showing that inhibition of AA-induced platelet aggregation on top of aspirin therapy was potentiated by EV-077. Furthermore, Rollini et al. 52 complemented these findings in patients with DM and stable CAD but on clopidogrel monotherapy by showing synergistic platelet inhibitory effects of EV-077 in vitro on multiple markers of platelet reactivity. An in vivo study of escalating doses of EV-077 administered as an oral solution was well tolerated and easily absorbed by healthy volunteers 53. EV-077 is in clinical phase II development. Overall, the pivotal role of the TP signaling pathway makes its blockade a rationale target. However, despite the sound early phase investigations with numerous TP antagonists, the results from clinical investigations evaluating TP antagonists have been disappointing. The reasons behind this remain unclear and may be attributed to multiple factors. These include studies conducted with a class of drugs in an early phase of development, inadequate design of clinical trials, or wrong study population. Indeed, the development of newer agents within this class may represent a promising avenue for future investigation, which, however, needs to be supported by convincing safety and efficacy data from appropriately designed randomized clinical trials. Oxidative stress and isoprostanes ROS, including superoxide anions and peroxides, are short-lived but highly bioactive and are usually formed during physiologic processes to regulate important functions of the body, such as redox homeostasis, cellular signaling, and innate immune response 54. Oxidative stress occurs in response to injury or to altered metabolic state as a result of an excessive formation of bioactive oxidation products with respect to the capacity of the endogenous scavenging mechanism and is dangerous to tissues by damaging lipids, proteins, carbohydrates, and DNA, influencing gene expression, cell growth, or apoptosis 54. Key events in the clinical manifestation of atherosclerosis, such as endothelial dysfunction, LDL oxidation, inflammation, and altered balance between vascular SMC proliferation and apoptosis, are strongly linked to oxidative stress (Fig. 3). Figure 3Open in figure viewerPowerPoint Main sources of oxidative stress and consequent vascular alterations. Usually, low-density lipoproteins (LDL) are protected from oxidative modification by the anti-oxidant system. However, several exogenous and endogenous factors can alter the redox state by inducing several enzyme systems in the vasculature (endothelial cells, EC; smooth muscle cells, SMC; or macrophages) to generate reactive oxygen species (ROS). ROS in the subendothelial space oxidize LDL (oxLDL), which induce the adhesion and entry of circulating monocytes (and other inflammatory cells) across the endothelium. Monocytes are differentiated by oxLDL into macrophages, which, following ingestion of oxLDL through scavenger receptors, transform into foam cells. Migration of foam cells and SMC into the neointima and SMC proliferation contribute to atherogenesis. A vicious cycle occurs, as foam cells release inflammatory cytokines while oxLDL contribute to endothelial dysfunction, ROS formation and production of isoprostanes (Iso-P). In human vessels, ECs are the major source of ROS 55. After entering the arterial lesion, LDL react with ROS and form oxidized LDL (oxLDL), which are involved in endothelial dysfunction, migration of SMC and macrophages, and release of inflammatory cytokines; oxLDL are internalized by macrophages and induce further oxidative stress to the ECs, SMCs, and foams cells, in a harmful, vicious cycle. Beyond being involved in aggregation and interaction with vascular surfaces, human platelets produce ROS, contributing to the propagation of atherogenesis 56. Oxidative stress increases the production of isoprostanes 57, which are produced in vivo at levels that largely exceed that of the highly unstable TXA2 (30-s half-life). Although the target of isoprostanes is periodically a matter of debate 58, it has been convincingly demonstrated that they act through TP receptor in in vivo experiments in mice 59. F2-isoprostanes can be easily quantified in human plasma or urine as an accurate circulating indicator of in vivo systemic oxidative stress with respect to the normal levels in healthy humans 57. Their overproduction has been observed in disorders characterized by vascular pathology or cardiovascular risk factors. The most abundant isoprostane, 8-iso-PGF2α, amplifies agonist-induced platelet aggregation and interaction with immobilized fibrinogen 60, mediates potent vasoconstriction in a variety of vascular beds, including kidneys, lung, heart, and brain 12, induces vascular SMC mitogenesis 61, mediates neutrophil adhesion to EC induced by minimally modified LDL 62, and induces death of vascular EC isolated from retinal vessels of newborn rats and pigs 63. The major urinary metabolite of 8-iso-PGF2α, 2,3-dinor-5,6-dihydro-15-F(2t)-isoprostane, arising from free radical–induced oxidation of gamma-linolenic acid, is a potent vasoconstrictor of retinal and brain microvessels through interaction with TP receptor 64. In vivo formation of the F2-isoprostanes is increased in patients with hypercholesterolemia, with significant linear correlation with LDL cholesterol content and 11-dehydro-TXB2 excretion 65, 66. F2-isoprostanes are enriched in coronary arteries from CAD 67 and in human atherosclerotic plaques, at the level of the lipid-rich core, associated with monocytes/macrophages, and of the subendothelium, associated with roundish and elongated foam cells 68. Lipid peroxydation plays a key role also in DM, where formation and urinary excretion of 8-iso-PGF2α are elevated and correlate with impaired glycemic control 7 corroborating the existence of a link with persistent platelet activation 69. Furthermore, in type 1 DM, enhanced lipid peroxidation and platelet activation represent early events that are possibly related to an acute inflammatory response, as DM children showed elevated levels of circulating interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and CRP 70. Urinary levels of F2-isoprostane are elevated in pulmonary hypertension 71, in renovascular 72 but not in essential systemic hypertension 72, 73, and in obesity 74 and cigarette smoking 75. The observation that cessation of smoking, weight loss, and physical exercise were associated with decreased production of F2-isoprostanes is suggestive of the existence of a causal relationship between these variables 76, 77. Despite many experimental and observational studies demonstrated the important role of oxidative stress in the pathogenesis of cardiovascular diseases, it must be emphasized that there is insufficient evidence from clinical trials to support the use of antioxidant supplementation for the prevention of cardiovascular diseases 78, 79. Vascular inflammation Endothelial cells In animal models, TP receptor antagonism preserves endothelium-dependent relaxation of isolated vessels 80, while studies in patients with CAD have shown that the administration of terutroban improved endothelial function 81. Beyond endothelium-dependent vasoactivity, TXA2 and isoprostanes increase EC expression of proinflammatory markers 82, while TP receptor antagonists inhibit proin
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