EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin

Sakariassen, Kjell S.; Femia, Eti Alessandra; Daray, Federico Manuel; Podda, Gian Marco; Razzari, Cristina; Pugliano, Mariateresa; Errasti, Andrea Emilse; Armesto, Arnaldo; Nowak, W; Alberts, Pēteris; Meyer, J.‐P.; Sorensen, Alexandra Santana; Cattaneo, Marco; Rothlin, Rodolfo Pedro

doi:10.1016/j.thromres.2012.08.309

Cited by 14 publications

(13 citation statements)

References 40 publications

(56 reference statements)

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“…Simultaneous administration of SQ29548 abolished the vasoconstrictor effect of both isoprostanes indicating a TP receptor-dependent mechanism (Möbert et al, 1997). This pro-vasoconstrictor potential of 8-iso-PGF2α and 8-iso-PGE2 has been confirmed in a wide range of different blood vessels, from human umbilical arteries, chicken embryo ductus arteriosus, pulmonary artery, femoral artery and porcine arteries to bovine coronary arteries, demonstrating the general vasoconstrictor potential of isoprostanes (Kromer and Tippins, 1996;van der Sterren and Villamor, 2011;Sakariassen et al, 2012). Interestingly, no vasoconstriction was induced in bovine coronary arteries indicating a putative speciesdependent functionality of 8-iso-PGF2α (Kromer and Tippins, 1996).…”

Section: Isoprostanes Act As Vasoconstrictorsmentioning

confidence: 70%

“…Interestingly, no vasoconstriction was induced in bovine coronary arteries indicating a putative speciesdependent functionality of 8-iso-PGF2α (Kromer and Tippins, 1996). The vasoconstrictor effect of isoprostanes, such as 8-iso-PGF2α and 8-iso-PGE2, is mainly mediated via TP receptors leading to the release of internally sequestered Ca 2+ and activation of the RhoA/Rho kinase 1 and 2 signalling pathway (Kromer and Tippins, 1996;Möbert et al, 1997;Mueed et al, 2008;Sakariassen et al, 2012). On the other hand, bovine aortic ECs possess two distinct binding sites for isoprostanes, indicating that the vasoconstrictor effect of these PG-like compounds may also be mediated by a so far not identified TP receptor-related isoprostane receptor (Yura et al, 1999;van der Sterren and Villamor, 2011).…”

Section: Isoprostanes Act As Vasoconstrictorsmentioning

confidence: 99%

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Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A₂ receptor activation

Bauer

Ripperger

Frantz

et al. 2014

British J Pharmacology

136

109

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Isoprostanes are free radical-catalysed PG-like products of unsaturated fatty acids, such as arachidonic acid, which are widely recognized as reliable markers of systemic lipid peroxidation and oxidative stress in vivo. Moreover, activation of enzymes, such as COX-2, may contribute to isoprostane formation. Indeed, formation of isoprostanes is considerably increased in various diseases which have been linked to oxidative stress, such as cardiovascular disease (CVD), and may predict the atherosclerotic burden and the risk of cardiovascular complications in the latter patients. In addition, several isoprostanes may directly contribute to the functional consequences of oxidant stress via activation of the TxA2 prostanoid receptor (TP), for example, by affecting endothelial cell function and regeneration, vascular tone, haemostasis and ischaemia/reperfusion injury. In this context, experimental and clinical data suggest that selected isoprostanes may represent important alternative activators of the TP receptor when endogenous TxA2 levels are low, for example, in aspirin-treated individuals with CVD. In this review, we will summarize the current understanding of isoprostane formation, biochemistry and (patho) physiology in the cardiovascular context. IntroductionOxidative stress in biological systems is defined as an imbalance between the generation of reactive oxygen species (ROS) and antioxidant defence mechanisms (Dalle-Donne et al., 2006;Giustarini et al., 2009). In contrast to the physiological condition, during which ROS are only present at moderate levels and play an important role as messengers in redox signalling, in pathological conditions, when the physiological redox state of cells is disturbed, ROS can severely affect cellular signalling and function. Indeed, ROS which are not neutralized or scavenged by antioxidant molecules, such as GSH or superoxide dismutase, may react with nucleic acids and proteins and thereby alter the biochemical and physical properties of these important cellular components. Moreover, exposure of lipids to free radicals induces a non-enzymatic reaction cascade resulting in an increased formation of bioactive molecules named isoprostanes. Consequently, systemic isoprostane formation is significantly increased in a variety of pathological processes associated with oxidative stress, for example, cancer as well as, cardiovascular, metabolic and neurodegenerative diseases, and isoprostanes are increasingly recognized not only as markers of oxidative stress but also as mediators of disease progression (Praticò et al., 1997;Reilly et al., 1998;Davì et al., 1999;Minuz et al., 2002;Vassalle et al., 2003;Schwedhelm et al., 2004, Xia et al., 2005Montuschi et al., 2007;Schwedhelm et al., 2010; Barocas et al., 2011;Davies and Roberts, 2011; KhademAnsari et al., 2011;Montine et al., 2011;Sbardella et al., 2013). Isoprostanes are PG-like compounds derived from lipid peroxidation of esterified unsaturated fatty acids, for example, arachidonic acid, which are primarily generated in a free rad...

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Section: Isoprostanes Act As Vasoconstrictorsmentioning

confidence: 70%

Section: Isoprostanes Act As Vasoconstrictorsmentioning

confidence: 99%

Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A₂ receptor activation

Bauer

Ripperger

Frantz

et al. 2014

British J Pharmacology

136

109

View full text Add to dashboard Cite

show abstract

“…Moreover, Sakariassen et al . 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 .…”

Section: Role Of Tp Receptor Activation In Thrombosis: Pharmacologicamentioning

confidence: 99%

“…Role of TP receptor activation in thrombosis: pharmacological and clinical effects of TP antagonists TXA 2 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].…”

Section: Abnormalities Of the Platelet Tp Receptor In Patients With Dmentioning

confidence: 99%

Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation

Capra

Bäck

Angiolillo

et al. 2014

Journal of Thrombosis and Haemostasis

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To cite this article: Capra V, B€ ack M, Angiolillo DJ, Cattaneo M, Sakariassen KS. Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation. J Thromb Haemost 2014; 12: 126-37.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 A 2 and its endoperoxide precursors, prostaglandin G 2 and H 2 , 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 A 2 . 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.

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“…It is interesting that both lumiracoxib (withdrawn for hepatotoxicity) and diclofenac display TP inhibition at high dosage, suggesting that pharmacologic derivatives might possess both coxib and TP activities [46,49]. A dual TXA2 synthase inhibitor/TP antagonist blocked the aggregation of diabetic platelets better than aspirin and decreased isoprostane-induced arterial contraction [50].…”

Section: Effects Of Inhibitors Of Prostanoid Synthesis On Blood Vessementioning

confidence: 99%

Prostanoids and NSAIDs in Cardiovascular Biology and Disease

Weksler

2015

Curr Atheroscler Rep

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Prostanoids and related arachidonic acid derivatives are important physiologic modulators in arteries, as well as mediators of inflammation, hemostasis, and cell proliferation. Their participation in atherosclerosis and in acute thrombotic events is complex, as demonstrated by untoward cardiovascular (CV) effects associated with clinical use of inhibitors of prostaglandin synthesis for treatment of chronic pain, inflammatory states, or cancer prophylaxis. Newer understanding of the pathophysiology of atherosclerosis and the pharmacology of prostanoids promises potential resolution of current problems resulting from the hazards of available prostanoid-altering drugs.

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EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin

Cited by 14 publications

References 40 publications

Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A₂ receptor activation

Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A₂ receptor activation

Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation

Prostanoids and NSAIDs in Cardiovascular Biology and Disease

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EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin

Cited by 14 publications

References 40 publications

Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A2 receptor activation

Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A2 receptor activation

Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation

Prostanoids and NSAIDs in Cardiovascular Biology and Disease

Contact Info

Product

Resources

About

Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A₂ receptor activation

Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A₂ receptor activation