Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect - Reduction of MRNA levels for interleukin-1 beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary endothelial cells

We examined the effects of four 3-hydroxy-3-methylglutaryl coenzyme A (HMG- CoA) reductase inhibitors (pravastatin, simvastatin, fluvastatin, and ceriv astatin) on the production and expression of inflammatory cytokines and on enzyme expression involving prostaglandin and superoxide production in cult ured human umbilical vein endothelial cells (HUVEC). All HMG-CoA reductase inhibitors significantly reduced interleukin-1 beta and -6 mRNA expression and their protein levels in the culture medium, and also inhibited cyclooxy genase-2 mRNA expression and their protein levels. And these drugs induced peroxisome proliferator-activated receptor alpha (PPAR alpha) and PPAR gamm a mRNA expression and their protein levels in HUVEC and hepatocyte. Moreove r the mRNA levels of p22phox, a 22-kD subunit and the protein levels of p47 phox, a 47-kD subunit of nicotine adenine dinucleotide phosphate (NADPH) ox idase, was decreased by treatment with either simvastatin, fluvastatin or c erivastatin, and this effect was reversed by mevalonate, geranylgeraniol, f arnesol, and cholesterol. The changes induced by HMG-CoA reductase inhibito rs might be due to regulation of cellular cholesterol content level, cellul ar cholesterol metabolic pathway, and cellular PPAR alpha activity, which w as related with inflammation. This unique anti-inflammatory effect in addit ion to its hypolipidemic action, may be beneficial in preventing the vascul ar complications that are induced by hyperlipidemia. (C) 2000 Elsevier Scie nce Inc. All rights reserved.