Endothelial nitric oxide synthase plays a minor role in inhibition of arterial thrombus formation

Özüyaman, Burcin; Gödecke, Axel; Küsters, Susanne; Kirchhoff, Elisabeth; Scharf, Rüdiger E.; Schrader, Jürgen

doi:10.1160/th03-09-0588

Cited by 63 publications

(61 citation statements)

References 27 publications

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“…Indeed, no difference in endothelial nitric oxide synthase expression of COX-2 and WT aortas was observed ( Figure X in the online-only Data Supplement). In addition, a reduction of endothelial nitric oxide synthase does not modify ferric chloride-induced arterial thrombosis, 42 but it paradoxically prolonged the time to occlusion. 43 …”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner

et al. 2012

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Background-Selective inhibitors of cyclooxygenase (COX)-2 increase the risk of myocardial infarction and thrombotic events, but the responsible mechanisms are not fully understood. Methods and Results-We found that ferric chloride-induced arterial thrombus formation was significantly greater in COX-2 knockout compared with wild-type mice. Cross-transfusion experiments excluded the likelihood that COX-2 knockout platelets, despite enhanced aggregation responses to collagen and thrombin, are responsible for increased arterial thrombus formation in COX-2 knockout mice. Importantly, we observed that COX-2 deletion decreased prostacyclin synthase and production and peroxisome proliferator-activated receptor-and sirtuin-1 (SIRT1) expression, with consequent increased upregulation of tissue factor (TF), the primary initiator of blood coagulation. Treatment of wild-type mice with a prostacyclin receptor antagonist or a peroxisome proliferator-activated receptor-␦ antagonist, which predisposes to arterial thrombosis, decreased SIRT1 expression and increased TF activity. Conversely, exogenous prostacyclin or peroxisome proliferator-activated receptor-␦ agonist completely reversed the thrombotic phenotype in COX-2 knockout mice, restoring normal SIRT1 levels and reducing TF activity. Furthermore, inhibition of SIRT1 increased TF expression and activity and promoted generation of occlusive thrombi in wild-type mice, whereas SIRT1 activation was sufficient to decrease abnormal TF activity and prothrombotic status in COX-2 knockout mice. Conclusions-Modulation of SIRT1 and hence TF by prostacyclin/peroxisome proliferator-activated receptor-␦ pathways not only represents a new mechanism in controlling arterial thrombus formation but also might be a useful target for therapeutic intervention in the atherothrombotic complications associated with COX-2 inhibitors. (Circulation. 2012; 126:1373-1384.)Key Words: blood coagulation Ⅲ carotid arteries Ⅲ prostacyclin Ⅲ signal transduction Ⅲ thrombosis P rostanoids are a family of bioactive lipid mediators formed from arachidonic acid by cyclooxygenases (COXs; COX-1 and COX-2). 1 Prostanoids are involved in a variety of physiological activities, including platelet aggregation, vasorelaxation and vasoconstriction, local inflammatory response, and leukocyte-endothelial cell adhesion. 2,3 In this context, prostanoids modulate the pathogenesis of vascular diseases such as arterial thrombosis and atherosclerosis. 4 The role of COX-2 in atherothrombosis is complex. This enzyme generates not only proinflammatory, but also anti-inflammatory prostanoids, such as prostacyclin (PGI 2 ), which, under certain conditions, may counteract platelet-derived thromboxane (TXA 2 ). 5 PGI 2 is a potent vasodilator and an inhibitor of platelet aggregation, leukocyte adhesion, and vascular smooth muscle cell proliferation. 6 These actions of PGI 2 are mediated through specific cell surface receptors known as PGI 2 receptors (IPs). Each IP is a 7-membrane-spanning G-protein-coupled receptor that elicits cAMP p...

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Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner

et al. 2012

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“…NO inhibits coagulation (12), and diabetes leads to fibrin deposition in glomeruli (13). eNOS −/− mice made diabetic by low doses of streptozotocin have increased fibrin deposition and tissue factor (TF, F3) expression in their glomeruli (11).…”

Section: Survival Of F1 (B6 × 129) Heterozygous Enosmentioning

confidence: 99%

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

Wang

Hiller

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Polymorphisms in the human endothelial nitric oxide synthase (eNOS) gene ( NOS3 ) have been associated with advanced nephropathy in diabetic patients and with decreased expression in tissue culture. However, direct proof that modest genetic decreases in eNOS expression worsen diabetic nephropathy is lacking. To investigate this effect, we took advantage of the hybrid vigor and genetic uniformity of the F1 progeny (eNOS +/+ , eNOS +/− , or eNOS −/− with or without diabetes) of a cross between heterozygous 129S6/SvEvTac eNOS +/− inbred females and heterozygous C57BL/6J eNOS +/− inbred males carrying the dominant Akita diabetogenic mutation Ins2 C96Y/+ . Whereas all C57BL/6J inbred eNOS −/− and eNOS +/− diabetic mice died before 5 mo, almost half of the F1 hybrid eNOS −/− and eNOS +/− diabetic mice lived until killed at 7 mo. Heterozygous eNOS +/− diabetic mice expressed ∼35% eNOS mRNA in the kidney and ∼25% glomerular eNOS protein relative to their eNOS +/+ diabetic littermates. These decreases in eNOS elevated blood pressure (BP) but not blood glucose. Urinary albumin excretion, mesangial expansion, glomerulosclerosis, mesangiolysis, and glomerular filtration rate increased in the order: eNOS +/+ Akita < eNOS +/− Akita < eNOS −/− Akita, independently of BP. Glomerular basement membrane thickening depended on increased BP. Renal expression of tissue factor and other inflammatory factors increased with the nephropathy; Nos2 also increased. Surprisingly, however, decreased eNOS expression ameliorated the increases in oxidative stress and tubulointerstitial fibrosis caused by diabetes. Our data demonstrate that a modest decrease in eNOS, comparable to that associated with human NOS3 variants, is sufficient to enhance diabetic nephropathy independently of its effects on BP.

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“…a significant antithrombotic effect, 15,16 studies suggesting that the absence of platelet eNOS has little consequence on arterial thrombus formation, 32,33 and even studies showing an impaired ability of eNOS −/− mice to form occlusive thrombi. 34 Differences in experimental conditions and animal models may probably explain the conflicting results.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

Momi

Caracchini

Falcinelli

et al. 2014

ATVB

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H ypertension is associated with an increased risk of arterial thrombotic events, such as stroke and myocardial infarction, 1 in which platelets are deeply involved. Previous studies have shown that β-adrenoceptor blockers reduce platelet activation and aggregation, 2 but this does not seem to be a class effect because not all β-blockers share this property. 3 dl-Nebivolol (a racemic mixture of d-and l-nebivolol) is a third-generation β 1 adrenoceptor-selective antagonist that, besides its β-blockade-mediated hypotensive effect, possesses direct vasodilatory properties through a mechanism involving the l-arginine/nitric oxide (NO) pathway. 4,5 Of the 2 enantiomers forming the racemic mixture of dl-nebivolol, d-nebivolol, which has an ≈200-fold greater affinity for β 1 -adrenoceptors than that of l-nebivolol, seems to be mainly responsible of selective β-blockade, 6 whereas the l-form is the main effector of the endothelium-dependent vasorelaxant effect. 7,8 dl-Nebivolol exerts its vasodilatory action by activating endothelial nitric oxide synthase (eNOS) and by preventing eNOS uncoupling, thus enhancing NO production. 9 Endothelium-derived NO is a powerful inhibitor of platelet activation and an antithrombotic agent. 10,11 Besides endothelium, eNOS is present in other cells, including platelets, [12][13][14] and several in vitro and in vivo observations in animals and in humans suggest that platelet-derived NO plays a significant anti-inflammatory and antithrombotic role. [15][16][17][18][19] dl-Nebivolol was previously reported to inhibit ADP-and collagen-induced aggregation of human platelets in vitro, 20 an effect prevented by the previous exposure of platelets to a NOS inhibitor, such as L-NG-nitroarginine methyl ester, and enhanced by preincubation with l-arginine, the substrate of NOS, suggesting that the antiplatelet effect of dl-nebivolol is mediated by an enhanced release of NO from platelets. 4 © 2014 American Heart Association, Inc. Objective-dl-Nebivolol, a selective β1-adrenergic receptor antagonist, besides its hypotensive activity exerts vasodilatory and platelet inhibitory effects in vitro by a mechanism involving nitric oxide (NO). Our aim was to evaluate whether nebivolol exerts in vivo antithrombotic effects, to unravel the mechanism of this action and to clarify the relative roles of its 2 enantiomers: d-and l-nebivolol. Methods and Results-In wild-type mice, dl-nebivolol, l-nebivolol, and d-nebivolol, but not bisoprolol, reduced mortality consequent to platelet pulmonary thromboembolism induced by the intravenous injection of collagen plus epinephrine (−44%, −45%, −29%, respectively; P<0.05), whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were effective. dl-Nebivolol, l-and d-nebivolol reduced photochemical damage-induced femoral artery thrombosis in wild-type mice, whereas in eNOS −/− mice only dl-nebivolol and d-nebivolol were active. Moreover, dl-nebivolol and l-nebivolol increased plasma, urinary-, and platelet-derived nitrites and nitrates (NOx), NO degradation products, in ...

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Endothelial nitric oxide synthase plays a minor role in inhibition of arterial thrombus formation

Cited by 63 publications

References 27 publications

Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner

Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

Stimulation of Platelet Nitric Oxide Production by Nebivolol Prevents Thrombosis

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