Pathogenesis of atherosclerosis and the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

Corsini, A.; Raiteri, M.; RSOMA, M; Zimetti, Francesca; Fumagalli, R.; Paoletti, Roberto

doi:10.1016/s0002-9149(06)80005-6

Cited by 16 publications

(32 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…28 Assuming that a high proportion of patients may have been under therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, as our usual recommended therapy, may give rise to the speculation about the direct role of some of these agents in attenuating smooth muscle cell proliferation. 29,30 However, similar paradoxical findings have been reported previously 23 as well, which may suggest that lipids may not act in the same manner in restenosis as in atherosclerosis.…”

Section: Discussionsupporting

confidence: 64%

Interlesion Dependence of the Risk for Restenosis in Patients With Coronary Stent Placement in Multiple Lesions

Kastrati

Schömig²,

Elezi³

et al. 1998

Circulation

View full text Add to dashboard Cite

Background-Little is known about the behavior with regard to restenosis of multiple lesions within the same patient treated with intracoronary stenting. Our objective was to test the hypothesis that there is an intrapatient dependence of restenosis between lesions. Methods and Results-Quantitative analysis was carried out on angiograms obtained before, immediately after, and at 6 months after coronary stent placement in 1734 lesions in 1244 patients. We used a specialized logistic regression that not only accounts for intraclass correlation but also quantifies it in the form of odds ratio (OR) as the change in risk of a lesion to develop restenosis if another companion lesion had restenosis. The model was based on 23 patient-and lesion-related variables with binary restenosis (diameter stenosis Ն50%) as end point. The overall restenosis rate was 27.5%: 24.4% for single-lesion, 28.6% for double-lesion, and 33.8% for Ն3-lesion interventions. After adjustment for the influence of significant factors (hypercholesterolemia, systemic arterial hypertension, diabetes mellitus, previous PTCA, ostial lesion, location in left anterior descending coronary artery, number of stents placed, vessel size, stenosis severity, balloon-to-vessel ratio, and final result), the analysis found a significant intrapatient correlation, OR 2.5 (1.8 to 3.6). This means that in patients with multilesion interventions, the risk of a lesion to develop restenosis is 2.5 times higher if a companion lesion has restenosis, independently of the presence or absence of analyzed patient risk factors (eg, diabetes). Conclusions-This study demonstrates that there is a dependence of restenosis between coronary lesions in patients who undergo a multilesion intervention. The likelihood of restenosis for a lesion is higher when another companion lesion has also developed restenosis. Other, as yet unidentified patient factors may be the source of this intrapatient correlation of restenosis.

show abstract

Section: Discussionsupporting

confidence: 64%

Interlesion Dependence of the Risk for Restenosis in Patients With Coronary Stent Placement in Multiple Lesions

Kastrati

Schömig²,

Elezi³

et al. 1998

Circulation

View full text Add to dashboard Cite

show abstract

“…7 Treatment with TPA increased MMP-9 activity Ͼ50%, and fluvastatin was still effective in inhibiting the enhanced protease activity by almost 50% ( Figure 2B). Our previous data have shown that fluvastatin may directly interfere with the major processes of atherogenesis occurring in the arterial wall 20 through the inhibition of the isoprenoid pathway. Because mevalonate is the precursor of isoprenic compounds, we postulated that the inhibitory effect of fluvastatin might be due to a deprivation of mevalonate caused by the drug.…”

Section: Resultsmentioning

confidence: 99%

“…20 SMC migration and proliferation are inhibited by the drug, 21,22 and cholesterol accumulation is prevented in macrophages 23 by reducing modified-LDL endocytosis. 24 Interestingly, the inhibitory activity observed in macrophages was more pronounced in cholesterol-loaded cells than in normal cells, suggesting a potential selectivity of the drug for the foam cells and hence for the atherosclerotic lesion.…”

mentioning

confidence: 99%

HMG-CoA Reductase Inhibitors Reduce MMP-9 Secretion by Macrophages

Bellosta

Via

Canavesi

et al. 1998

ATVB

469

281

View full text Add to dashboard Cite

Abstract-Macrophages secrete matrix metalloproteinases (MMPs) that may weaken the fibrous cap of atherosclerotic plaque, predisposing its fissuration. The 92-kDa gelatinase B (MMP-9) has been identified in abdominal aortic aneurysms and in atherosclerotic tissues. Fluvastatin, through the inhibition of the isoprenoid pathway, inhibits major processes of atherogenesis in experimental models (smooth muscle cell migration and proliferation and cholesterol accumulation in macrophages). We studied the effect of fluvastatin on the activity of MMP-9 in mouse and human macrophages in culture. Conditioned media of cells treated for 24 hours with fluvastatin were analyzed by gelatin zymography. In mouse macrophages, fluvastatin (5 to 100 mol/L) significantly inhibited in a dose-dependent manner MMP-9 activity from 20% to 40% versus control. The drug, at a concentration as low as 5 mol/L, inhibited MMP-9 activity (Ϸ30%) in human monocyte-derived macrophages as well. Phorbol esters (TPA, 50 ng/mL) stimulated MMP-9 activity by 50%, and fluvastatin inhibited this enhanced activity up to 50% in both mouse and human macrophages. The above results on the secretion of MMP-9 were confirmed by Western blotting and ELISA. The inhibitory effect of fluvastatin was overcome by the simultaneous addition of exogenous mevalonate (100 mol/L), a precursor of isoprenoids. Fluvastatin's effect was fully reversible, and the drug did not cause any cellular toxicity. The statin did not block directly the in vitro activation of the secreted protease. Similar data were obtained with simvastatin. Altogether, our data indicate an inhibition of MMP-9 secretion by the drug. This effect is mediated by the inhibition of synthesis of mevalonate, a precursor of numerous derivatives essential for several cellular functions. (Arterioscler Thromb Vasc

show abstract

“…To this end, human peripheral blood mononuclear cells (PBMC) and human endothelial cells (EC) were treated for 24 hours with increasing concentrations of lipophilic inhibitors of HMG-CoA reductase, lovastatin or simvastatin (0.1-40 M), before the exposure to inflammatory stimuli. Pravastatin, a hydrophilic statin, was not considered for these studies because of its reported lack of activity in vitro on smooth muscle cell migration, proliferation, and apoptosis (Corsini et al, 1995b(Corsini et al, , 1998Guijarro et al, 1998) and for its weaker inhibitory effect on sterol synthesis (Kurakata et al, 1996;van Vliet et al, 1996). As shown in Figure 1A, lovastatin and simvastatin, at 10 and 40 M, significantly reduced MCP-1 production induced in PBMC by 100 ng/ml LPS ( p Յ 0.01, Student's t test) or 0.005 KE/ml inactivated Streptococcus hemoliticus ( p Յ 0.01, Student's t test), whereas doses below 10 M were ineffective.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Monocyte Chemotactic Protein-1 Synthesis by Statins

Romano

Diomede

Sironi

et al. 2000

Laboratory Investigation

281

141

View full text Add to dashboard Cite

SUMMARY:The beneficial effects of statins on the reduction of cardiovascular events has been partly attributed to their anti-inflammatory properties. In the complex of the different pathogenetic events leading to atherosclerosis, recent data suggest a central role of monocyte chemotactic protein-1 (MCP-1), because mice knock-out for MCP-1 or its receptor CC-chemokine receptor 2 were considerably resistant to plaque formation. In this study we investigated the effect of different statins on in vitro and in vivo production of MCP-1. Lovastatin and simvastatin caused a dose-dependent inhibition of MCP-1 production in peripheral blood mononuclear cells exposed to lipopolysaccharide or inactivated Streptococcus hemoliticus and in human endothelial cells exposed to interleukin-1␤. The addition of mevalonate overrode the inhibitory effect of statins indicating that mevalonate-derived products are important for chemokine production. The in vivo anti-inflammatory effect of statins was investigated using the mouse air-pouch model of local inflammation. Lovastatin and pravastatin were orally administered to mice according to a treatment schedule that significantly inhibited the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity without affecting total blood cholesterol. At the dose of 10 mg/kg, lovastatin and pravastatin reduced by approximately 50% the lipopolysaccharide-induced leukocytes recruitment and the exudate MCP-1 production. In conclusion, statins, by inhibiting mevalonate-derived products, reduced both in vitro and in vivo the production of chemokines involved in leukocyte migration, and this effect is unrelated to their cholesterol-lowering action. (Lab Invest 2000, 80:1095-1100.

show abstract

Pathogenesis of atherosclerosis and the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

Cited by 16 publications

References 0 publications

Interlesion Dependence of the Risk for Restenosis in Patients With Coronary Stent Placement in Multiple Lesions

Interlesion Dependence of the Risk for Restenosis in Patients With Coronary Stent Placement in Multiple Lesions

HMG-CoA Reductase Inhibitors Reduce MMP-9 Secretion by Macrophages

Inhibition of Monocyte Chemotactic Protein-1 Synthesis by Statins

Contact Info

Product

Resources

About