Simvastatin Preserves the Ischemic-Reperfused Myocardium in Normocholesterolemic Rat Hearts

Lefer, Allan M.; Campbell, Barry; Shin, Yong-Kyoo; Scalia, Rosario; Hayward, Reid; Lefer, David J.

doi:10.1161/01.cir.100.2.178

Cited by 305 publications

(234 citation statements)

References 39 publications

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“…Whereas the cardioprotective effects of statins, independent of their hypolipidaemic effects, have already been demonstrated in several normocholesterolaemic models [14,15,38], this is the first animal study demonstrating the pleiotropic effects of statins in a model characterised by increased LDL-cholesterol levels.…”

Section: Effect Of Atorvastatin On Lipid Profilementioning

confidence: 78%

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

et al. 2007

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Aims/hypothesis Emerging evidence suggests that statins exert beneficial effects beyond those predicted by their cholesterollowering actions. We investigated whether atorvastatin influences the development of left ventricular (LV) dysfunction, independently of cholesterol-lowering, in an experimental model of type 1 diabetes mellitus cardiomyopathy. Methods Streptozotocin-induced diabetic rats were treated with atorvastatin (50 mg/kg daily, orally) or with vehicle for 6 weeks. LV function was analysed using tip-catheter measurements. Cardiac stainings of TNF-α, IL-1β, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, CD11a/lymphocyte-associated antigen-1, CD11b/ macrophage antigen alpha, CD18/β2-integrin, ED1/CD68, collagen I and III, and Sirius Red were assessed by digital image analysis. Ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) activities were determined by RAC1 glutathione-S-transferasep21-activated kinase and rhotekin pull-down assays, respectively. Cardiac lipid peroxides were measured by a colorimetric assay. The phosphorylation state of p38 mitogen-activated protein kinase (MAPK) and endothelial nitric oxide synthase (eNOS) protein production were analysed by western blot. Results Diabetes was associated with induced cardiac stainings of TNF-α, IL-1β, cellular adhesion molecules, increased leucocyte infiltration, macrophage residence and cardiac collagen content. In contrast, atorvastatin reduced both intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function. This effect was paralleled with a normalisation of diabetes-induced RAC1 and RHOA activity, in the absence of LDL-cholesterol lowering. In addition, atorvastatin decreased diabetesinduced cardiac lipid peroxide levels and p38 MAPK phosphorylation by 1.3-fold (p<0.05) and 3.2-fold (p<0.0005), respectively, and normalised the reduced eNOS production caused by diabetes. Conclusions/interpretation These data indicate that atorvastatin, independently of its LDL-cholesterol-lowering capacity, reduces intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function in an experimental model of diabetic cardiomyopathy.

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Section: Effect Of Atorvastatin On Lipid Profilementioning

confidence: 78%

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

et al. 2007

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“…Skeletal muscle injury, measured by edema, leucosequestration and electrical properties, were significantly lower with pravastatin pretreatment than in the untreated group. Although previous work has demonstrated the anti-inflammatory properties of pravastatin in renal and cardiac models of ischemia reperfusion injury, its effect on skeletal muscle ischemia reperfusion has not been studied previously (Lefer et al 1999, Joyce et al 2001.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is believed that statins have anti-inflammatory properties independent of their cholesterol-lowering properties, and have indeed been shown to attenuate renal and cardiac injury in a number of models of ischemia reperfusion (Lefer et al 1999, Joyce et al 2001. Furthermore, statins have been shown to inhibit the generation of superoxide in activated neutrophils by reducing tyrosine phosphorylation, and to reduce endotoxin-induced leukocyte endothelial cell interactions (Kanno et al 1999, Pruefer et al 2002.…”

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confidence: 99%

Pravastatin attenuates tourniquet-induced skeletal muscle ischemia reperfusion injury

et al. 2006

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Background Revascularization of a limb following prolonged ischemia results in substantial skeletal muscle injury. Statins play a well-understood role in the treatment of hypercholesterolemia but are also known to have anti-inflammatory properties. The purpose of this study was to examine the effects of pravastatin pre-treatment in the setting of skeletal muscle ischemia reperfusion injury (IRI).Methods Adult male Sprague Dawley rats (n = 27) were randomized into 3 groups: control group, I/R group, IR group pre-treated with pravastatin. Bilateral hind-limb ischemia was induced by rubber band application proximal to the level of the greater trochanters for 2.5 h. Treatment groups received normal saline in equal volumes prior to tourniquet release. Following 12 h reperfusion, the tibialis anterior muscle was dissected and muscle function assessed electrophysiologically by electrical field stimulation. The animals were then killed and skeletal muscle harvested for evaluation.Results We found that pre-treatment with pravastatin reduces the tissue oxidative damage and edema associated with skeletal muscle reperfusion injury. Skeletal muscle injury, measured by edema, leucosequestration and electrical properties were significantly lower with pravastatin pre-treatment compared to the non-treated group.Interpretation We feel that pravastatin pre-treatment may be a potential therapeutic intervention for skeletal muscle ischemia reperfusion injury in the clinical setting.

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“…41,42 CD18 was evaluated by direct immunofluorescence staining of whole blood using an established lyse/wash procedure (BD PharMingen, Franklin Lakes, NJ). After the deep anesthesia, the whole blood anti-coagulated with ethylenediaminetetraacetic acid was obtained from each of six rats in the simvastatin (25 mg/kg/day)-treated, vehicle-treated, and nondiabetic control groups.…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

Miyahara

Kiryu

Yamashiro

et al. 2004

The American Journal of Pathology

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Simvastatin Preserves the Ischemic-Reperfused Myocardium in Normocholesterolemic Rat Hearts

Cited by 305 publications

References 39 publications

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

Pravastatin attenuates tourniquet-induced skeletal muscle ischemia reperfusion injury

Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

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