HMG-CoA Reductase Inhibitors Regulate Inflammatory Transcription Factors in Human Endothelial and Vascular Smooth Muscle Cells

Abstract

Objective-Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. Methods and Results-Simvastatin, atorvastatin, and lovastatin (0.1 to 10 mol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-B) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay ( Key Words: statins Ⅲ nuclear factor-B Ⅲ activator protein-1 Ⅲ hypoxia-inducible factor-1␣ Ⅲ vascular endothelial growth factor R andomized clinical trials have clearly shown the benefit of statin therapy in the reduction of cardiovascular events and total mortality in coronary heart disease patients with either high or normal cholesterol levels. 1 In these studies, survival curves began to diverge within a relatively short period of time and before effects on plaque size were likely to occur. Demonstrated effects of HMG-CoA reductase inhibitors were not reflected by a regression in coronary stenoses as assessed by angiography. These findings have suggested that mechanisms of statins beyond lipid lowering are likely to be involved in the reduction of coronary events. 2 Both in vivo and in vitro studies support the notion that statins counteract the chronic subclinical vascular inflammatory state associated with atherosclerosis. 3,4 Statins inhibit leukocyte-endothelium interaction 5-7 and decrease inflammation in carotid lesions in humans. 8 Many of the vasculoprotective effects of HMG-CoA reductase inhibitors seem to be mediated by enhanced availability of nitric oxide. 9 There is increasing evidence that statins may act on the transcriptional level as well, eg, simvastatin inhibited endothelial secretion of PAI-1, which was correlated with reduced mRNA transcription and activity of the promoter. 10 Despite extensive research on molecular mechanisms of statins, little is known about the interactions of these drugs with transcription factors. The aim of this study was to characterize the effects of simvastatin, atorvastatin, and lovastatin on the activation of nuclear factor (NF)-B, activator protein (AP)-1, and hypoxia-inducible factor (HIF)-1␣ in endothelial and arterial smooth muscle cells. Because these factors regulate the transcription of many genes, including cytokines, chemokines, adhesion molecules, and growth factors, such interactions of statins on vascular cell signaling and gene expression may explain atheroprotective effects not directly related to cholesterol lowering. MethodsSimvastatin (MSD) and lovastatin (Calbiochem) prodrugs were activated from their inactive lactone proforms to their active dihy-

Varicose Remodeling of Veins Is Suppressed by 3‐Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Inhibitors

“…In this context, we showed that the transcriptional activity of AP‐1 appeared to be rate‐limiting for the development of varicose‐like veins and thus may represent a druggable target. To translate our findings into a therapeutic approach, we tested the capacity of HMG‐CoA reductase inhibitors to interfere with venous remodeling because these drugs have been reported to attenuate AP‐1 activity 13. Subsequent in vitro experiments revealed that treatment with atorvastatin or rosuvastatin, but not simvastatin, inhibited the activity of AP‐1 in HUVSMCs that were exposed to biomechanical stretch (Figure 1A).…”

“…Considering arterial diseases, statins have repeatedly been reported to counteract progression of arterial diseases and reduce the 5‐year incidence of major coronary events or stroke,23, 24 effects that may be exerted independently from their HMG‐CoA reductase inhibitory capacity. A pleiotropic effect mediated by this class of drugs is inhibition of the activity of transcription factors such as AP‐1 or nuclear factor‐κB,13 which control expression of genes that have been associated with pathological vascular remodeling processes25, 26, 27 and responses of vascular cells to elevated biomechanical stress 28. Accordingly, atorvastatin and especially rosuvastatin, which is a more potent and water‐soluble inhibitor of HMG‐CoA reductase, inhibited proliferation of AP‐1 activity in stretch‐stimulated venous SMCs as well as expression of its target genes MCP1 and MMP2 in isolated perfused veins exposed to supraphysiological pressure levels.…”

A new systolic parameter defined as the ratio of brachial pre-ejection period to brachial ejection time predicts overall and cardiovascular mortality in hemodialysis patients

“…[23][24][25][26] Hemodialysis patients are usually prescribed many of these medications for cardiovascular causes. In this study, patients in the mortality group had a higher percentage of having received aspirin or ACEI and/or ARB therapy.…”

Atorvastatin prevents hypoxia-induced inhibition of endothelial nitric oxide synthase expression but does not affect heme oxygenase-1 in human microvascular endothelial cells

“…It can be hypothesized that this is due to the inhibition of the activity of inflammatory transcription factors, such us NFκB or AP-1, by statins [23].…”