Simvastatin Exerts Both Anti-inflammatory and Cardioprotective Effects in Apolipoprotein E–Deficient Mice

Scalia, Rosario; Gooszen, Michael E.; Jones, Steven P.; Hoffmeyer, Michaela R.; Rimmer, David M.; Trocha, Steven D.; Huang, Paul L.; Smith, Marion B.; Lefer, Allan M.; Lefer, David J.

doi:10.1161/01.cir.103.21.2598

Cited by 191 publications

(152 citation statements)

References 28 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…This appears to be in contrast to previous reports demonstrating impaired endothelium-dependent vasorelaxation and reduced concentration of NO derived from the aorta of the atherosclerotic mouse (Barton et al, 1998;Jiang et al, 2000;Scalia et al, 2001). However, in the isolated whole heart preparation, it cannot be determined whether the released NO X is derived from the coronary vessels or the myocardium.…”

Section: Discussioncontrasting

confidence: 90%

Cardioprotective effect of an endothelin receptor antagonist during ischaemia/reperfusion in the severely atherosclerotic mouse heart

Gonon

Bulhak

Bröijersén

et al. 2005

British J Pharmacology

View full text Add to dashboard Cite

1 Endothelin (ET) receptor antagonists are cardioprotective during myocardial ischaemia and reperfusion through a nitric oxide (NO)-dependent mechanism. The aim of the present study was to investigate whether the ET receptor antagonist, bosentan, is cardioprotective in atherosclerotic mice. 2 Buffer-perfused hearts from apolipoprotein E/LDL receptor double knockout (KO) and wild-type (WT) mice were subjected to global ischaemia and reperfusion. 3 Following reperfusion, the recovery of rate-pressure product (RPP; left ventricular developed pressure (LVDP) Â heart rate) was equally impaired in WT and KO mice given vehicle (3478 and 2979%, respectively). The ET A /ET B receptor antagonist bosentan (10 mmol l À1 ) improved recoveries to 57710% in WT and to 68710% in KO mice (Po0.01). Similar effects were observed for the recovery of left ventricular end-diastolic pressure (LVEDP), developed pressure and dP/dt. 4 Bosentan improved the recovery of coronary flow in both KO and WT mice. Recovery of coronary flow was significantly higher in the KO mice given bosentan (135715%) than in the WT group (111712%; Po0.01). ET-1 (1 nmol l À1 ) impaired recovery of coronary flow in both WT and KO mice though this effect was more pronounced in the KO mice (Po0.01). 5 Coronary outflow of NO during reperfusion was enhanced in both KO and WT mice following bosentan administration. 6 The ET A /ET B receptor antagonist bosentan protects the atherosclerotic mouse heart from ischaemia/reperfusion injury. The observation that ET receptor blockade and stimulation have a greater effect on coronary flow in atherosclerotic hearts indicates an increased activation of the ET system in atherosclerotic coronary arteries.

show abstract

Section: Discussioncontrasting

confidence: 90%

Cardioprotective effect of an endothelin receptor antagonist during ischaemia/reperfusion in the severely atherosclerotic mouse heart

Gonon

Bulhak

Bröijersén

et al. 2005

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Statins are known to attenuate the recruitment of circulating leukocytes to endothelium including leukocytes rolling, adhesion, and transmigration [2,4,5,15,27], which represents a hallmark of vascular inflammation. Previous studies are limited to the impact of statins on ICAM-1, VCAM-1, E-selectin and P-selectin [2,16,17,27,28] which are inducible endothelial CAMs with functional relevance confined to leukocyte tethering and adhesion [29].…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, the pleiotropic effects of statins, including a wide variety of vascular effects such as inhibiting vascular inflammation, have been recognized [2][3][4][5]. The effects of statins, for example, upregulation of eNOS expression, have been attributed to the inhibition of Rho protein [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Although various reports have shown that statins can reduce cell adhesion and transmigration [2,4,15], so far studies uncovering the endothelial responses to statin treatment at the molecular level have been limited to the expression of cell adhesion molecules such as VCAM-1, ICAM-1 and E-selectin, etc. [16,17], which are involved in leukocytes tethering and adhesion to endothelium, the mechanism of statinsÕ inhibitory effect on TEM at the molecular level, however, has yet to be explored.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Statin‐inhibited endothelial permeability could be associated with its effect on PECAM‐1 in endothelial cells

Wei¹,

Lü²,

Song³

et al. 2005

FEBS Letters

View full text Add to dashboard Cite

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to inhibit leukocyte recruitment to endothelium but the mechanism is less understood. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an endothelial junction protein involved in leukocyte diapedesis. We hypothesize that in endothelial cells, statins may well recruit PECAM-1 to exert their inhibitory effect on leukocyte transendothelial migration (TEM). In lovastatin-treated resting human umbilical vein endothelial cells (HUVECs), increased levels of mRNA and protein of PECAM-1 as well as its bio-synthesis (all 2-fold) were observed by real-time PCR, Western blotting and 35 S-labeled methionine incorporation assay, respectively. Moreover, in lovastatin treated resting cells as well as TNF-a activated endothelial cells, unanimously decreased Triton X-100 insoluble and soluble PECAM-1 ratio was observed. Such changes were accompanied by decreased TEM of U-937 cells (a promonocyte cell line). All lovastatinÕs effects were abrogated by mevalonic acid. In resting HUVECs, geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP) (both are isoprenoid intermediates in the cholesterol biosynthesis pathway) compromised the effect of lovastatin on PECAM-1 expression, whereas C3 toxin, an inhibitor of small G proteins, exerted statin-like effect.Conclusion: Statin-reduced endothelial permeability could be attributed to altered intracellular distribution of PECAM-1 in endothelial cells. We speculate that lovastatin regulates PE-CAM-1 expression in HUVECs through the mevalonate-GGPP pathway by inhibiting of Rho small GTPase.

show abstract

“…Statins have also been shown to modify the function of ECs, smooth muscle cells, platelets, and monocytes/macrophages (22). Their effects include decreasing the expression of adhesion molecules in monocytes and leukocyte-endothelial interactions (23)(24)(25)(26), inhibiting platelet function (27), inhibiting tissue factor expression by mononuclear cells (28,29), down-regulating inflammatory cytokines in ECs (30), increasing fibrinolytic activity (31,32), and immunomodulation by decreasing the expression of class II major histocompatibility complex antigen (33).…”

Section: Conclusion These Findings Indicate That Fluvastatin Signifimentioning

confidence: 99%

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Ferrara¹,

Liu²,

Espinola³

et al. 2003

Arthritis & Rheumatism

138

View full text Add to dashboard Cite

Methods. Two groups of CD-1 male mice, each comprising ϳ18 mice, were fed either normal saline solution or 15 mg/kg fluvastatin for 15 days. Each of the 2 groups was further subdivided to receive either purified IgG from patients with the antiphospholipid syndrome (IgG-APS) or normal IgG from healthy subjects. Analysis of thrombus dynamics was performed in treated and control mice, using a standardized thrombogenic injury procedure, and the area (size) of the thrombus was measured. Adhesion of leukocytes to ECs was analyzed with a microcirculation model of exposed cremaster muscle. Baseline and posttreatment soluble intercellular adhesion molecule 1 (sICAM-1) levels were determined by enzyme-linked immunosorbent assay.Results. IgG-APS mice treated with fluvastatin showed significantly smaller thrombi, a reduced number of adherent leukocytes, and decreased levels of sICAM-1 compared with IgG-APS animals treated with placebo.Conclusion. These findings indicate that fluvastatin significantly diminishes aPL-mediated thrombosis and EC activation in vivo. These results may have important implications for the design of new treatment strategies aimed at preventing recurrent thrombosis in patients with APS.

show abstract

Simvastatin Exerts Both Anti-inflammatory and Cardioprotective Effects in Apolipoprotein E–Deficient Mice

Abstract: Simvastatin attenuates leukocyte-endothelial cell interactions and ameliorates ischemic injury in hypercholesterolemic mice independently of lipid-lowering actions.

Cited by 191 publications

References 28 publications

Cardioprotective effect of an endothelin receptor antagonist during ischaemia/reperfusion in the severely atherosclerotic mouse heart

Cardioprotective effect of an endothelin receptor antagonist during ischaemia/reperfusion in the severely atherosclerotic mouse heart

Statin‐inhibited endothelial permeability could be associated with its effect on PECAM‐1 in endothelial cells

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Contact Info

Product

Resources

About