ArticleThe Biochemical journal2007
Fluvastatin inhibits regulated secretion of endothelial cell von Willebrand factor in response to diverse secretagogues.
Article in The Biochemical journal, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 25 citations in OpenAlex.
- Androgen-Independent Prostate Cancer Is Sensitive to CDC42-PAK7 Kinase Inhibition.Biomedicines · 2022Article
- Cardiac implications of thrombotic thrombocytopenic purpura.World journal of cardiology · 2018Review
- Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells.Scientific reports · 2016Article
- Cdc42 GTPases facilitate TNF-α-mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells.Journal of the peripheral nervous system : JPNS · 2013Article
- Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials.Current pharmaceutical design · 2012Review
- Beneficial vasoactive endothelial effects of fluvastatin: focus on prostacyclin and nitric oxide.Heart and vessels · 2011Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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