Lovastatin inhibits oxidized L-A-phosphatidylcholine B-arachidonoyl-gamma-palmitoyl (ox-PAPC)-stimulated interleukin-8 mRNA and protein synthesis in human aortic endothelial cells by depleting stores of geranylgeranyl pyrophosphate.
Human aortic endothelial cells (HAEC) exposed to 50 microg/ml oxidized L-A-phosphatidylcholine B-arachidonoyl-gamma-palmitoyl (ox-PAPC) for 6h increased in interleukin-8 mRNA and protein levels. Preincubation of HAEC with the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) inhibitor, (20 microM), significantly inhibited ox-PAPC-stimulated interleukin-8 mRNA and protein levels. Mevalonate (200 microM) reversed the inhibition of ox-PAPC-stimulated mRNA and protein levels by lovastatin, indicating the inhibitory effect of lovastatin was due to inhibition of mevalonate synthesis. Addition of the geranylgeraniol (GGOL, 10 microM) but not farnesol (FOL, 10 microM), reversed the inhibitory effect of lovastatin on interleukin-8 mRNA and protein levels stimulated by ox-PAPC, indicating that lovastatin exerted its effect by inhibiting stores of geranylgeranyl pyrophosphate (GGPP) which are necessary for geranylgeranylation of proteins. These results suggest a new mechanism for lovastatin in preventing atherosclerosis by inhibiting the inflammatory response that takes place in the vascular wall.
Dvoracek
Lucas A
LA
Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV 26074, USA.
Kreisberg
Jeffrey I
JI
McKinney
Jordan
J
Schmid
Gabrielle
G
Francis
Amanda D
AD
Kacmarik
Katie L
KL
Lee
Huey Miin
HM
Detrick
Melinda S
MS
Primerano
Donald A
DA
Santanam
Nalini
N
Kreisberg
Robert
R
D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D008148:Lovastatin / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000494:pharmacology*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000187:drug effects*
D016209:Interleukin-8; D010713:Phosphatidylcholines; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D008148:Lovastatin; C002963:geranylgeranyl pyrophosphate