Lovastatin controls signal transduction in vascular smooth muscle cells by modulating phosphorylation levels of mevalonate-independent pathways.
Lovastatin has been proven to effectively lower circulating LDL cholesterol and to exert antiproliferative effects on various cell lines, the latter effect being only incompletely understood. We found that lovastatin modulates the signal transducing phosphorylation cascade in vascular smooth muscle cells in a mevalonate-independent manner. Lovastatin was found to distinctively increase total phosphotyrosine levels in smooth muscle cells, an effect which could not be restored by mevalonate. At a concentration of 5 micromol/L lovastatin had a highly specific effect on the mitogen-activated protein kinase pathway. The expression of p42/44 mitogen-activated protein kinase (MAPK) was clearly reduced, but could be restored by addition of mevalonate, while the phosphorylation of p44 was mildly suppressed and the phosphorylation of p42 MAPK was reduced to non-detectable levels. While the phosphorylation of p44 MAPK could partially be restored by addition of mevalonate, the reduced phosphorylation of p42 MAPK could not be restored by addition of excessive doses of mevalonate or stimulation of the cells with basic fibroblast growth factor. Concurrently the expression of the GTP-binding Ras protein was significantly elevated at 5 and 20 micromol/L lovastatin, this effect being attenuated by addition of mevalonate to cell cultures. The data indicate that lovastatin is capable of modulating cellular signaling independently of the cholesterol synthesis pathway.
Sindermann
J R
JR
Institute for Arteriosclerosis Research, University of Münster, Germany.
Schmidt
A
A
Breithardt
G
G
Buddecke
E
E
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002417:Cattle; D018929:Cell Culture Techniques; D003331:Coronary Vessels / Q000166:cytology* / Q000187:drug effects*; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D018631:ras Proteins / Q000187:drug effects / Q000502:physiology
D000924:Anticholesteremic Agents; D008148:Lovastatin; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; D008798:Mevalonic Acid