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Published on: November 10, 2017
Statins differ in their ability to block NF-kappaB activation in human blood monocytes
A Hilgendorff1, H Muth, B Parviz
1Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
Insights
Statins vary in their ability to reduce inflammation by inhibiting NF-kappaB activation. Cerivastatin demonstrated significantly greater potency in preventing NF-kappaB activation compared to other statins tested.
Area of Science:
- Cardiovascular Medicine
- Molecular Biology
- Immunology
Background:
- Statin therapy benefits cardiovascular health through lipid-lowering and anti-inflammatory effects.
- The anti-inflammatory mechanisms of statins are not fully understood, with inconsistent effects on inflammatory markers.
- Nuclear factor-kappa B (NF-kappaB) is a key transcription factor in inflammatory pathways.
Purpose of the Study:
- To investigate and compare the effectiveness of different statins in preventing NF-kappaB activation.
- To elucidate the differential anti-inflammatory properties of statins beyond cholesterol reduction.
Main Methods:
- Six statins were tested for their ability to inhibit NF-kappaB induction in human monocytes stimulated with lipopolysaccharide (LPS).
- Assays included electrophoretic mobility shift assay (EMSA) for NF-kappaB binding activity, Western blotting for IkappaB-alpha, and reverse transcription-quantitative polymerase chain reaction (rtPCR) for tissue factor mRNA.
- Tissue factor (TF) activity was measured using a clotting assay.
Main Results:
- All tested statins inhibited LPS-induced NF-kappaB activation in a dose-dependent manner, primarily by preventing IkappaB phosphorylation and degradation.
- Significant differences in inhibitory potency were observed among statins, with cerivastatin being the most potent inhibitor.
- The potency ranking of statins for inhibiting NF-kappaB activation was Cer > Atv > Sim > Pra > Lov > Flu, correlating with effects on tissue factor expression.
Conclusions:
- Statins exhibit varying potency in interfering with NF-kappaB signaling in human monocytes.
- These findings support the hypothesis that certain statins possess stronger anti-inflammatory effects than others, independent of their lipid-lowering capacity.
Objective:
The benefits of statin therapy in cardiovascular medicine are ascribed to its lipid-lowering effect as well as its anti-inflammatory properties. Whereas all statins have been shown to reduce cholesterol plasma levels, their effect on inflammatory markers has been inconsistent. Here, we show that statins differ markedly in their effectiveness in preventing activation of NF-kappaB, a transcription factor involved in the activation of immediately early genes during inflammation.
Methods:
Six statins (atorvastatin (Atv), cerivastatin (Cer), fluvastatin (Flu), lovastatin (Lov), pravastatin (Pra), simvastatin (Sim)) were tested for their ability to influence the induction of NF-kappaB in human monocytes (Mo) during inflammation. Mo isolated from healthy blood donors were incubated with LPS (10 microg/ml) in the presence and absence of statin (0.001-5 microM). NF-kappaB binding activity (EMSA), degradation and phosphorylation of the inhibitor protein IkappaB-alpha (Western blotting), tissue factor (TF) mRNA (rtPCR), and TF activity (clotting assay) were analyzed.
Results:
All statins inhibited LPS-induced NF-kappaB binding activity in Mo in a dose-dependent manner. The inhibitory effect was due to reduced phosphorylation and degradation of the NF-kappaB inhibitor protein IkappaB, and was primarily dependent on the absence of mevalonate. Whilst this effect appeared with all statins, there were marked differences in the degree of inhibition between the statins. Cer (45 +/- 9% inhibition, p < 0.05) was 9-fold more effective in reducing NF-kappaB activation than Flu (5 +/- 10% inhibition). The differences in the potency of statins (Cer > Atv > Sim > Pra > Lov > Flu) were also reflected at the transcriptional level and the protein level of NF-kappaB controlled tissue factor expression.
Conclusions:
The finding that statins differ in their potency in interfering with the activation of NF-kappaB signaling in human monocytes further supports the hypothesis that some statins inhibit the inflammatory response more than others.
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