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

Abstract

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.

Fluvastatin upregulates endothelial nitric oxide synthase activity via enhancement of its phosphorylation and expression and via an increase in tetrahydrobiopterin in vascular endothelial cells

“…However, fluvastatin's influence on eNOS activity and expression was already described in endothelial cells [27][28][29]. Harris et al [27] reported acute effect of statin on eNOS phosphorylation and activity, while Fish et al [28] reported the increased expression of eNOS by fluvastatin. Meda et al [29] included importance of statin-induced tetrahydrobiopterin (BH4) in their report.…”

Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease

“…Another explanation may be that at the time of inclusion, all patients with CVD used statins that are known to decrease VWF levels, probably by influencing VWF secretion. 23,24 Therefore, use of statins may have attenuated the association between genetic variation and VWF:Ag levels. Thus far, SNP rs1063857 was associated with an increase in VWF:Ag levels and with the risk for disease in 2 independent studies, which suggests that VWF may be a causal factor in the development of CVD.…”

Atorvastatin Reduces the Proadhesive and Prothrombotic Endothelial Cell Phenotype Induced by Cocaine and Plasma From Cocaine Consumers In Vitro

“…Statins, however, improve several EC functions, 19 including the secretion of VWF from EC stimulated with thrombin. 27 Here, we report on the effect of atorvastatin on VWF release and platelet adhesion to HUVEC on exposure to cocaine and plasma from chronic cocaine consumers.…”