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_5 label "Selventa" provenance.
_4 value "Many of the cholesterol-independent properties of statins are linked to their property to inhibit the synthesis of isoprenoids involved in Ras and Rho activation. Cyclooxygenase(COX)-2 expression has increased in the atherosclerotic lesions where it colocalizes with MMP-9. Recent insights suggest the involvement of Rho-dependent pathway in the activation of COX-2. Therefore, we decided to investigate the effect of statins on COX-2 and MMPs stimulated expression in human umbilical vein endothelial cell (HUVEC). Methods: Simvastatin was incubated with HUVEC for 6 h, followed by stimulation with tumor necrosis factor or phorbol myristate acetate (PMA) for 12 h. Then, COX-2 activity and protein were assessed and zymography analysis were performed to verify the effect of statin on metalloproteinases secretion. At 0.1-10 micromol/L, simvastatin reduced COX-2 expression without affects COX-I expression. The effect of simvastatin on COX-2 protein expression was totally reversed by the addition of mevalonate and geranylgeranylpyrophosphate, but not by farnesylpyrophosphate indicating the possible involvement of geranylated proteins, as Rho, in the signal transduction pathway leading to COX-2 expression. Confirm to this was obtained by the similarity of statin's effect with inhibitors of geranylgeranyltransferase. COX activity, as 6-keto-PGF1alpha production, was (pg/1000 cells) 0.22 +/- 0.01 in control conditions, 4.88 +/- 1.72 after PMA, 2.60 +/- 1.34 after PMA in the presence of simvastatin (P<0.01 vs PMA). The same statin treatment also reduced, in an isoprenoid-dependent manner, the PMA stimulated release of MMP-9. A functional link between COX-2 activity and MMP-9 release was likely, since COX-2 inhibition by compound NS-398 reduced the expression of MM P-9. Conclusions: Statins reduce the expression and activity of COX-2 linked to the release of MMP-9 in human vascular endothelial cells. These effects may contribute to cholesterol-unrelated vasculoprotective effects of statin treatment, including effects on plaque stability." provenance.
_4 wasQuotedFrom _3 provenance.
assertion hadPrimarySource _3 provenance.
large_corpus.bel title "BEL Framework Large Corpus Document" provenance.
_3 title "AHA Abstracts 77" provenance.
large_corpus.bel description "Approximately 61,000 statements." provenance.
assertion wasDerivedFrom large_corpus.bel provenance.
assertion wasDerivedFrom _4 provenance.
large_corpus.bel authoredBy _5 provenance.
large_corpus.bel version "20131211" provenance.
_3 identifier "AHA Abstracts 77" provenance.
_3 type "Other" provenance.