The regulation of endothelial VWF secretion by nitric oxide: is it physiological?

Zarei, Seyed Zeinolabedin; Frieden, Maud; Kaufmann, J. E.; Vischer, Ulrich M.

doi:10.1111/j.1538-7836.2005.01626.x

Cited by 7 publications

(8 citation statements)

References 14 publications

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“…Endothelial dysfunction and activation, vascular aging, and arterial stiffness are all associated with increased levels of VWF [16, 17]. Nitric oxide (NO), a marker of endothelial health, exerts an inhibitory effect on VWF release by ECs, probably blocking the granule membrane fusion process or inhibiting calcium mobilization from WPBs [15, 18, 19]. Endothelial dysfunction probably represents the background that links VWF, inflammation, and thrombosis [18–20].…”

Section: Pathophysiology Of Vwf In the Bloodstreammentioning

confidence: 99%

The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy

Gragnano

Sperlongano

Golia

et al. 2017

Mediators of Inflammation

174

162

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Beyond its role in hemostasis, von Willebrand factor (VWF) is an emerging mediator of vascular inflammation. Recent studies highlight the involvement of VWF and its regulator, ADAMTS13, in mechanisms that underlie vascular inflammation and immunothrombosis, like leukocyte rolling, adhesion, and extravasation; vascular permeability; ischemia/reperfusion injury; complements activation; and NETosis. The VWF/ADAMTS13 axis is implicated in the pathogenesis of atherosclerosis, promoting plaque formation and inflammation through macrophage and neutrophil recruitment in inflamed lesions. Moreover, VWF and ADAMTS13 have been recently proposed as prognostic biomarkers in cardiovascular, metabolic, and inflammatory diseases, such as diabetes, stroke, myocardial infarction, and sepsis. All these features make VWF an attractive therapeutic target in thromboinflammation. Several lines of research have recently investigated “tailor-made” inhibitors of VWF. Results from animal models and clinical studies support the potent anti-inflammatory and antithrombotic effect of VWF antagonism, providing reassuring data on its safety profile. This review describes the role of VWF in vascular inflammation “from bench to bedside” and provides an updated overview of the drugs that can directly interfere with the VWF/ADAMTS13 axis.

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Section: Pathophysiology Of Vwf In the Bloodstreammentioning

confidence: 99%

The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy

Gragnano

Sperlongano

Golia

et al. 2017

Mediators of Inflammation

174

162

View full text Add to dashboard Cite

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“…Calcium mobilization can be biphasic, reflecting release from intracellular stores and extracellular influx. Measurements of peak calcium and AUC (area under curves) account for these phases, which have both been correlated with regulated vWF secretion [12,23].…”

Section: Effects Of Fluvastatin On Intracellular Calciummentioning

confidence: 99%

“…Simvastatin inhibits thrombin-induced vWF secretion from cultured arterial ECs [11], partly in an NO-dependent manner. However, the physiological relevance of NO as a regulator of vWF secretion has been contested [12].…”

Section: Introductionmentioning

confidence: 99%

Fluvastatin inhibits regulated secretion of endothelial cell von Willebrand factor in response to diverse secretagogues

Fish

Hong

Viglino

et al. 2007

Biochemical Journal

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Regulated secretion of EC (endothelial cell) vWF (von Willebrand factor) is part of the haemostatic response. It occurs in response to secretagogues that raise intracellular calcium or cAMP. Statins are cholesterol-lowering drugs used for the treatment of cardiovascular disease. We studied the effect of fluvastatin on regulated secretion of vWF from HUVEC (human umbilical-vein ECs). Secretion in response to thrombin, a protease-activated receptor-1 agonist peptide, histamine, forskolin and adrenaline (epinephrine) was inhibited. This inhibition was reversed by mevalonate or geranylgeranyl pyrophosphate, and mimicked by a geranylgeranyl transferase inhibitor, demonstrating that the inhibitory mechanism includes inhibition of protein geranylgeranylation. To investigate this mechanism further, calcium handling and NO (nitric oxide) regulation were studied in fluvastatin-treated HUVEC. Intracellular calcium mobilization did not correlate with vWF secretion. Fluvastatin increased eNOS [endothelial NOS (NO synthase)] expression, but NOS inhibitors failed to reverse the effect of fluvastatin on vWF secretion. Exogenous NO did not inhibit thrombin-induced vWF secretion. Many small GTPases are geranylgeranylated and some are activated by secretagogues. We overexpressed DN (dominant negative) Rho GTPases, RhoA, Rac1 and Cdc42 (cell division cycle 42), in HUVEC. DNCdc42 conferred inhibition of thrombin- and forskolin-induced vWF secretion. We conclude that, via inhibition of protein geranylgeranylation, fluvastatin is a broadspectrum inhibitor of regulated vWF secretion. Geranylgeranylated small GTPases with functional roles in regulated secretion, such as Cdc42, are potential targets for the inhibitory activity of fluvastatin.

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“…VWF is released predominantly in response to a rise in cytosolic free calcium and cyclic adenosine monophosphate (cAMP) levels. cAMP levels are commonly regulated by stress hormones, such as epinephrine, and increased intracellular calcium (Ca2+) occurs in response to NO production [ 12 ]. However, far less is known about the levels of VWF in non-diabetic SCAD when acute stress factors are absent.…”

Section: Introductionmentioning

confidence: 99%

Low Paraoxonase 1 Arylesterase Activity and High von Willebrand Factor Levels are Associated with Severe Coronary Atherosclerosis in Patients with Non-Diabetic Stable Coronary Artery Disease

et al. 2014

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BackgroundParaoxonase 1 (PON1) activity and von Willebrand factor (VWF) release are associated with lesion initiation in atherosclerosis. Diabetes can complicate coronary artery disease (CAD) due to the production of advanced glycation end products. This study evaluated PON1 activity and VWF levels in non-post-acute coronary syndrome, stable CAD (SCAD) patients without diabetes.Material/MethodsNon-diabetic SCAD patients and patients experiencing acute stress periods were selected (n=130). Forty-seven cases with normal coronary angiography and 50 healthy individuals served as controls. The non-diabetic SCAD group was then stratified into single-vessel lesions, multiple-vessel lesions, and mild or severe luminal stenosis according to the number and the degree of luminal stenoses. Serum PON1 paraoxonase and arylesterase activities, and plasma VWF levels were measured, as well as serum total cholesterol, total triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apolipoprotein A1. PON1 arylesterase activity was detected with an ordinary chemistry system using a novel phenylacetate derivative.ResultsBoth PON1 paraoxonase and arylesterase were lower in the non-diabetic SCAD group, but VWF levels were higher (versus controls, all P<0.001). PON1 paraoxonase activity (OR=0.991), PON1 arylesterase activity (OR=0.981), and VWF (OR 2.854) influenced SCAD in multiple logistic regression. Decreased PON1 arylesterase activity and increased VWF levels were associated with severe atherosclerosis in non-diabetic SCAD patients. We also observed a slight negative correlation between VWF and PON1 paraoxonase/arylesterase.ConclusionsPON1 and VWF are detectable markers that may predict the severity of stenoses, ideally facilitating a non-diabetic SCAD diagnosis before the sudden onset of life-threatening symptoms.

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The regulation of endothelial VWF secretion by nitric oxide: is it physiological?

Cited by 7 publications

References 14 publications

The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy

The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy

Fluvastatin inhibits regulated secretion of endothelial cell von Willebrand factor in response to diverse secretagogues

Low Paraoxonase 1 Arylesterase Activity and High von Willebrand Factor Levels are Associated with Severe Coronary Atherosclerosis in Patients with Non-Diabetic Stable Coronary Artery Disease

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