High-dose lovastatin decreased basal prostacyclin production in cultured endothelial cells.
The effect of lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on prostacyclin production was studied in cultured human umbilical vein endothelial cells. The results indicated that lovastatin induced a significant dose- and time-dependent decrease of arachidonic acid release from the cells, an inhibition of phospholipase A(2) (PLA(2)) activity, a reduction of [(3)H]choline in lysophosphatidylcholine (lysoPC), and a diminishment of (45)Ca(2+) influx into the cells. The decreased arachidonic acid release was not reversed by addition of either intermediate products during cholesterol synthesis, such as mevalonate, geranylgeraniol, farnesol, or cholesterol and lipoprotein although a reduced concentration of cholesterol in the cells, caused by lovastatin, was reversed by added cholesterol. Lovastatin, furthermore, diminished prostacyclin production and inhibited activity of cyclooxygenase-1. 27-Hydroxycholesterol (27OHC), an oxidized cholesterol, had the same effect on HMG-CoA reductase as lovastatin, but 27OHC increased arachidonic acid release and (45)Ca(2+) influx. Our results indicated that lovastatin inhibited significantly activities of PLA(2) and cyclooxygenase-1, resulting in a marked reduction in arachidonic acid release, lysoPC content and prostacyclin production in the cultured vascular endothelial cells.
Zhou
Qi
Q
Burnsides Research Laboratory, Department of Veterinary Biosciences, 1208 W. Pennsylvania Avenue, Urbana, IL 61801, USA. szhou@uiuc.edu
Zhou
Yi
Y
Kummerow
Fred A
FA
D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D013997:Time Factors
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D008148:Lovastatin; D011464:Epoprostenol