Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis.
Restenosis remains the largest single obstacle to the long-term success of invasive vascular interventions. Lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin (2 microM) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32% respectively: this was not significantly different. Lovastatin (10 microM) reduced [methyl 3H]-thymidine uptake by 51% in saphenous vein-derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin-induced inhibition of vascular smooth muscle cell proliferation and [methyl 3H]-thymidine uptake was completely reversed by adding mevalonate (100 microM) but cholesterol (10-40 micrograms ml-1) had no effect. Isopentenyl adenine (25-50 microM) did not affect the inhibition of [methyl 3H]-thymidine uptake by lovastatin (10 microM), but farnesol (20 microM), another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect.
Munro
E
E
Department of Clinical Pharmacology, St Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, UK.
Patel
M
M
Chan
P
P
Betteridge
L
L
Clunn
G
G
Gallagher
K
K
Hughes
A
A
Schachter
M
M
Wolfe
J
J
Sever
P
P
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology*; D003327:Coronary Disease / Q000473:pathology*; D005204:Farnesol / Q000494:pharmacology; D006801:Humans; D007541:Isopentenyladenosine; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008148:Lovastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D012501:Saphenous Vein / Q000166:cytology
C001478:N(6)-(delta(2)-isopentenyl)adenine; D005204:Farnesol; D007541:Isopentenyladenosine; D002784:Cholesterol; D008148:Lovastatin; D007770:L-Lactate Dehydrogenase; D000225:Adenine; D008798:Mevalonic Acid