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

Dvoracek, Lucas A.; Kreisberg, Jeffrey I.; McKinney, Jordan; Schmid, Gabrielle; Francis, Amanda D.; Kacmarik, Katie L.; Lee, Huey Miin; Detrick, Melinda S.; Primerano, Donald A.; Santanam, Nalini; Kreisberg, Robert

doi:10.1016/j.atherosclerosis.2009.06.013

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Volume 208, Issue 1 , Pages 50-55, January 2010

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

Lucas A. Dvoracek
- Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV 26074, United States
Jeffrey I. Kreisberg
- Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV 26074, United States
Jordan McKinney
- Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV 26074, United States
Gabrielle Schmid
- Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV 26074, United States
Amanda D. Francis
- Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV 26074, United States
Katie L. Kacmarik
- Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV 26074, United States
Huey Miin Lee
- Department of Statistics, West Virginia University, Morgantown, WV 26506-6330, United States
Melinda S. Detrick
- Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV 26074, United States
Donald A. Primerano
- Department of Biochemistry and Microbiology, Marshall University, Huntington, WV 25755, United States
Nalini Santanam
- Department of Pharmacology, Physiology & Toxicology, Marshall University, Huntington, WV 25755, United States
Robert Kreisberg
- Department of Natural Sciences and Mathematics, West Liberty University, West Liberty, WV 26074, United States
- Corresponding author at: Department of Natural Sciences and Mathematics, West Liberty University, PO Box 295/route 88N, 139 Campus Service Center, West Liberty, WV 26074, United States. Tel.: +1 304 336 8052; fax: +1 304 336 8266.

Received 2 April 2009; received in revised form 11 May 2009; accepted 8 June 2009. published online 13 July 2009.

Abstract

Human aortic endothelial cells (HAEC) exposed to 50μg/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, (20μM), significantly inhibited ox-PAPC-stimulated interleukin-8 mRNA and protein levels. Mevalonate (200μM) 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, 10μM) but not farnesol (FOL, 10μM), 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.