Decreased C-reactive protein-induced resistin production in human monocytes by simvastatin.
BACKGROUND
Resistin is a novel cysteine-rich protein that plays a role in the development of insulin resistance and atherosclerosis in rodents, while its role in humans is unclear. C-reactive protein (CRP) is an important risk predictor for coronary heart disease, and it can also modify the expression of genes involved in atherogenesis. Statins have been demonstrated to possess lipid lowering effects as well as pleiotropic properties. We hypothesize that CRP may result in overexpression of resistin, and statin may decrease CRP-induced resistin expression in cultured human peripheral blood monocytes (PBMC).


OBJECTIVE
The aim of the present study, therefore, was to assess the effects of both CRP on resistin expression and simvastatin on CRP-induced of resistin expression in cultured human PBMC.


METHODS
Human PBMC were isolated from the whole blood of healthy volunteers by density gradient centrifugation. First, cells were incubated with varying concentrations of CRP (0, 5, 10, 25 and 50 microg/ml) for 24h for assessing the dose-dependent effects on resistin expression. Second, 25 microg/ml of CRP was used to time-dependent evaluation on resistin expression (0, 3, 6, 12 and 24h). Moreover, cells were pretreated with simvastatin at concentrations from 0.1 to 1 microM for 2h, and then co-incubated with 25 microg/ml CRP for 24h for evaluating effect of statin on resistin production subjected to CRP. Finally, in additional experiments, monocytes were incubated with 1 microM simvastatin in the absence or presence of 100 microM mevalonate or 10 microM geranylgeranyl-pyrophosphate (GGPP) or 10 microM farnesylpyrophosphate (FPP) for 2h, then co-incubated with CRP for 24h for examining whether effects of statin on CRP-induced resistin expression was independent of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.


RESULTS
The results showed that CRP induced both mRNA expression and protein secretion of resistin in a dose- and time-dependent manner. Co-incubation with simvastatin significantly inhibited CRP-induced up-regulation of mRNA and protein expression of resistin. Treatment with mevalonate, GGPP, but not FPP, reversed the inhibition of resistin expression caused by simvastatin, suggesting that simvastatin regulated resistin expression in culture human PBMC through the mevalonate-GGPP signal pathway.


CONCLUSIONS
In the present study, the data showed that CRP could significantly increase resistin expression in cultured human PBMC, and this effect was inhibited by simvastatin, suggesting that CRP and resistin might be involved in the pathogenesis of atherosclerosis, and statin therapy might be beneficial for atherosclerotic disease by modifying CRP-induced resistin overexpression in PBMC.
Hu
Wen-Lan
WL
Department of Cardiology, Fu Wai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, PR China.
Qiao
Shu-Bin
SB
Qian
Shu-Bing
SB
Li
Jian-Jun
JJ
D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy; D002097:C-Reactive Protein / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D003327:Coronary Disease / Q000097:blood / Q000188:drug therapy; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007333:Insulin Resistance; D008798:Mevalonic Acid / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D052243:Resistin / Q000096:biosynthesis*; D012307:Risk Factors; D012377:Rodentia; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D052243:Resistin; D002097:C-Reactive Protein; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid