Fluvastatin Inhibits Basal and Stimulated Plasminogen Activator Inhibitor 1, but Induces Tissue Type Plasminogen Activator in Cultured Human Endothelial Cells

Abstract

SummaryThe effects of fluvastatin, a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) inhibitor, on the biosynthesis of tissue plasminogen activator (t-PA) and of its major physiological inhibitor (plasminogen activator inhibitor type 1, PAI-1) were investigated in cultured human umbilical vein endothelial cells (HUVEC). Fluvastatin (0.1 to 2.5 µM), concentration-dependently reduced the release of PAI-1 antigen by unstimulated HUVEC, subsequent to a reduction in PAI-1 steady-state mRNA levels and de novo protein synthesis. In contrast, it increased t-PA secretion.The drug also reduced PAI-1 antigen secreted in response to 10 µg/ml bacterial lipopolysaccharide (LPS), 100 U/ml tumour necrosis factor α (TNFα) or 0.1 µM phorbol myristate acetate (PMA).Mevalonate (100 µM), a precursor of isoprenoids, added to cells simultaneously with fluvastatin, suppressed the effect of the drug on PAI-1 both in unstimulated and stimulated cells as well as on t-PA antigen. Among intermediates of the isoprenoid pathway, all-trans-geranylgeraniol (5 µM) but not farnesol (10 µM) prevented the effect of 2.5 µM fluvastatin on PAI-1 antigen, which suggests that the former intermediate of the isoprenoid synthesis is responsible for the observed effects.

Inflammation and the cardiovascular system

“…Furthermore, Wiesbauer et al and others showed that statins significantly reduced the IL-1a and TNF-a induced increase in PAI-1 in vascular cells. This supports the notion that HMG CoA reductase inhibitors might ameliorate the response of vascular cells toward activation by inflammatory cytokines [117,118,120].…”

“…The mechanism is due, in part, to the immunomodulatory ability of statins to decrease the expression of endothelial adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 and E-selectin [114,115]. Moreover, in vascular cell statins reduced PAI-1 and increased t-PA expression and in this way might exert their clinically proven beneficial effects by shifting the balance locally at the site of vascular lesions toward increased fibrinolysis thereby reducing the risk of thrombus formation at such sites [116][117][118][119][120]. Furthermore, Wiesbauer et al and others showed that statins significantly reduced the IL-1a and TNF-a induced increase in PAI-1 in vascular cells.…”

Lipid-independent effects of an estrogen–statin combination: inhibition of expression of adhesion molecules and plasminogen activator inhibitor-1 in human endothelial cell cultures

“…Mussoni and colleagues were also able to demonstrate an inhibitory effect of fluvastatin on PAI-1 in human vascular endothelial cells 22 .…”

“…Estradiol produced a significant decrease of PAI-1 by 8% (CI [4][5][6][7][8][9][10][11][12][13][14] and 22% (CI 14-28) at 0.1 and 1 mmol/l, respectively, with fluvastatin a reduction at 0.1 and 1 mmol/l was found, values being 16% (CI [12][13][14][15][16][17][18][19][20][21][22] respectively. These changes were significantly different, compared with the values for the monosubstances, at all concentrations.…”

Postprandial hypertriglyceridemia associated with inflammatory response and procoagulant state after a high-fat meal in hypertensive patients

“…PAI-1 is the principal inhibitor of the fibrinolytic system. It has been confirmed that CRP and TNFa can induce abnormal endothelial secretion in cultured endothelial cells, including Pselectin and PAI-1 [7][8][9][10][11], which could aggravate endothelial dysfunction.…”