HMG-CoA reductase inhibitors reduce IκB kinase activity induced by oxidative stress in monocytes and vascular smooth muscle cells

Reactive oxygen species, such as Superoxide an ion (O₂ ^-) and hydrogen peroxide (H₂O₂), may act as second messengers of intracellular signaling and play a key role in the pathogenesis of atherosclerosis. The nuclear factor κB (NF-κB) is a redox-sensitive transcription factor that is involved in this process. The aim of the present study was to investigate the molecular mechanisms of action of statins on cultured vascular smooth muscle cells (VSMC) and monocytic cells (THP-1) under oxidative stress. In THP-1 and cultured VSMC, O₂ ^- caused an increase in NF-κB activation (P < 0.05) that was correlated with inhibitory 1κB-α degradation. Atorvastatin or simvastatin decreased NF-κB activation induced by oxidative stress by around 50% in both cell types and was correlated with the 1κB-α levels. In monocytes, O₂^- increased IκB kinase (IKK)-1 and IKK-2 activity (P < 0.05) and p38 and p42/44 activation and phosphorylation, which was reduced by statins. PD 98059 (p42/44 inhibitor) and SB20358 (p38 inhibitor) decreased NF-κB binding activity and prevented 1κB-α degradation. However, we only observed a reduction in IKK-1 and IKK-2 activity with PD98059. Statins diminish NF-κB activation elicited by oxidative stress through the inhibition of IKK-1/-2, p38, and p42/44 activation. These data may help to further understand the molecular mechanisms of statins in cardiovascular disease.