Statins Inhibit Neutrophil Infiltration in Skeletal Muscle Reperfusion Injury (original) (raw)
Simvastatin induces impairment in skeletal muscle while heart is protected
Biochemical and biophysical research communications, 2005
3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are widely used to reduce plasma cholesterol concentration. However, statins are also known to induce various forms of muscular toxicity. We have previously shown that acute application of simvastatin on human skeletal muscle samples induced a cascade of cellular events originating from mitochondria and resulting in a global alteration of Ca2+ homeostasis. The present study was designed to further define the origin of the mitochondria impairment and to understand the apparent lack of deleterious effect on the heart. Using fluorescence imaging analysis and oxygraphy on human and rat skinned skeletal muscle samples, we show that the simvastatin-induced mitochondria impairment results from inhibition of the complex I of respiratory chain. Similar simvastatin-induced mitochondria impairment and alteration of Ca2+ homeostasis occur in permeabilized but not in intact ventricular rat cardiomyocytes. In intact rat skeletal...
Role of simvastatin in endotoxemia-induced muscle injury
2017
We aimed to investigate the role of prior treatment of simvastatin on cytokine response, energy levels, and apoptotic molecules on muscle tissue in rats treated with lipopolysaccharide (LPS) during the early phase of sepsis. Male Wistar albino rats (200-250 g) were divided into four groups: control, endotoxemia (20 mg/kg, i.p.), simvastatin (20 mg/kg, p.o.), and simvastatin + endotoxemia. Four hours after the beginning of the experiments, 8 rats from each group were sacrificied and gastrocnemius muscle tissue was dissected to examine for histologic changes using hematoxylin-eosin staining. The gene expressions of TNF-α, IL-10 and Bcl-2, Bax, and Caspase-3 mRNA levels were analyzed using real-time polymerase chain reaction. Creatine, creatine phosphate, adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) levels were investigated in muscle tissue using high performance liquid chromatography. ATP values were found low in the endotoxemia group an...
characteristics of statin‐induced muscle injury as well as clinical features of patients who develop this condition in terms of frequency and pattern of evolution. Materials and Methods: Forty patients (age 39‐74 years) including 25 subjects with type 2 diabetes mellitus, 9 with cardiovascular diseases and 6 with hyperlipidemia, who were receiving atrovastatin 40 mg/day for variable period, were studied. Thirty three healthy subjects (age 31‐74 years) served as control group. Creatine phosphokinease level, thyroid function, motor unit potential parameters and muscle fiber conduction velocity of biceps brachii and tibialis anterior muscles were measured. Results: Creatine phosphokinase level was elevated in statin users, particularly in those with diabetes mellitus. Less than 50% of statin users experienced symptoms related to muscle injury. Muscle fiber conduction velocity of the biceps brachii muscle was significantly reduced. Statin users with diabetes mellitus showed significant changes in electrophysiological parameters as compared to those with cardiovascular diseases and hyperlipidemia. Muscle biopsies showed muscle fiber variation in size, fibrosis and mild inflammatory cell infiltration. Immunohistochemical evaluation of muscle biopsies showed positive expression of Bcl‐2 and one patient showed positive P53 immunohistochemical expression with elevated level of creatine phosphokinase. Conclusion: Atorvastatin increased average creatine kinase, statins produce mild muscle injury even in asymptomatic subjects. Diabetic statin users were more prone to develop muscle injury than others. Muscle fiber conduction velocity evaluation is recommended as a simple and reliable test to diagnose statin‐induced myopathy instead of invasive muscle biopsy.
… and Vascular Biology, 2011
Objective-Clinical trials of statins during myocardial infarction (MI) have differed in their therapeutic regimes and generated conflicting results. This study evaluated the role of the timing and potency of statin therapy on its potential mechanisms of benefit during MI. Methods and Results-ST-elevation MI patients (nϭ125) were allocated into 5 groups: no statin; 20, 40, or 80 mg/day simvastatin starting at admission; or 80 mg/day simvastatin 48 hours after admission. After 7 days, all patients switched their treatment to 20 mg/day simvastatin for an additional 3 weeks and then underwent flow-mediated dilation in the brachial artery. As of the second day, C-reactive protein (CRP) differed between non-statin users (12.0Ϯ4.1 mg/L) and patients treated with 20 (8.5Ϯ4.0 mg/L), 40 (3.8Ϯ2.5 mg/L), and 80 mg/day (1.4Ϯ1.5 mg/L), and the daily differences remained significant until the seventh day (PϽ0.0001). The higher the statin dose, the lower the elevation of interleukin-2 and tumor necrosis factor-␣, the greater the reduction of 8-isoprostane and low-density lipoprotein(Ϫ), and the greater the increase in nitrate/nitrite levels during the first 5 days (PϽ0.001). Later initiation of statin was less effective than its early introduction in relation to attenuation of CRP, interleukin-2, tumor necrosis factor-␣, 8-isoprostane, and low-density lipoprotein(Ϫ), as well as in increase in nitrate/nitrite levels (PϽ0.0001). At the 30th day, there was no longer a difference in lipid profile or CRP between groups; the flow-mediated dilation, however, was proportional to the initial statin dose and was higher for those who started the treatment early (Pϭ0.001). Conclusion-This study demonstrates that the timing and potency of statin treatment during MI are key elements for their main mechanisms of benefit. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00906451.
Role of neutrophil-endothelial adhesion in skeletal muscle reperfusion injury
British Journal of Surgery, 1996
During postischaemic revascularization neutrophilendothelial adhesion in the skeletal muscle microcirculation, promoted by the neutrophil adhesion molecule Mac-1, may impair muscle blood flow and release oxygen free radicals and proteolytic enzymes which causes further tissue injury. This study has assessed the effect of an anti-Mac-1 monoclonal antibody on the severity of skeletal' muscle injury in a rat model of 6-h hindlimb ischaemia and 4-h reperfusion. In control animals a sustained impairment of muscle perfusion was associated with neutrophil sequestration, muscle infarction and muscle oedema (P < 0.001 versus normal rats). In contrast, intravenous administration of anti-Mac-1 monoclonal antibody before revascularization prevented neutrophil recruitment, reduced muscle necrosis and improved postischaemic muscle perfusion at 120 and 240 min (not significantly different from normal), thus confirming that neutrophils are important cellular mediators of skeletal muscle reperfusion injury. Monoclonal antibodies targeting neutrophil adhesion molecules may, therefore, have a role in the prevention of this complication of limb revascularization.
Cardiovascular Research, 2001
Objective: We tested the hypothesis of beneficial effects of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitor simvastatin in a model of ischemia-reperfusion, and investigated potential mechanisms. Methods: Isolated working rat hearts were subjected to 15 min global ischemia and 22-180 min reperfusion in the presence or absence of simvastatin (10-100 mM). We evaluated creatinephosphokinase and nitrite levels in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcribed polymerase chain reaction and Western blotting) in the presence or absence of the transcriptional inhibitor actinomycin-D. Results: Simvastatin (25 mM) significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. Protection became less evident at 50 mM and reverted to increased damage at 100 mM. At 25 mM, simvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, probably due to a post-transcriptional regulation since unaltered by animal pretreatment with actinomycin D. Simvastatin also significantly decreased iNOS √ mRNA and protein, as well as nitrite production after ischemia-reperfusion. The addition of the NOS inhibitor N-nitro-L-arginine methylester (L-NAME, 30 mM) to 25 mM simvastatin-treated hearts significantly reduced cardioprotection against ischemia-reperfusion. Conclusions: In this model, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant simvastatin concentration reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by cholesterolindependent, NO-dependent mechanisms.
Statin mediated protection of the ischemic myocardium
Vascular Pharmacology, 2005
Hypercholesterolemia is a major risk factor in the development of cardiovascular disease and HMG-CoA reductase inhibitors (i.e. statins) were originally designed to reduce serum cholesterol levels and thus reduce this risk factor. However, it has become increasingly apparent that the effects of statins extend well beyond their lipid lowering actions, and these pleiotropic effects have a major role in protecting the myocardium against ischemic injury. There have been a large number of clinical studies demonstrating the safety and efficacy of statins in reducing total mortality as well as many other secondary endpoint markers in patients with cardiovascular disease. In addition, statins appear to benefit patients with a variety of clinical conditions such as acute coronary syndromes and severe heart failure. Recent experimental studies demonstrated that stains can rapidly (i.e. within hours) upregulate endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production. These landmark studies of statins and eNOS function set the foundation for the investigation of the protective effects of statins. Many experimental studies investigating the effects of statins on eNOS and cardiac injury in the setting of ischemia and reperfusion have been performed in an attempt to determine the extent of the protection as well as the mechanism of the protection. This review article will focus on our current understanding of statin-mediated protection of the myocardium against ischemiareperfusion injury and infarction. D
Neutrophils and Skeletal Muscle Reperfusion Injury
Annals of the New York Academy of Sciences, 1994
Revascularization of ischemic skeletal muscle may lead to the development of skeletal muscle reperfusion injury (SMRI), which is characterized by muscle edema and muscle necrosis. Neutrophils have the ability to mediate tissue injury by the release of powerful cytotoxic oxidants and the proteolytic enzyme elastase, and they have been strongly implicated in the pathogenesis of this injury.' This study investigated the effect of both neutropenia and the specific inhibition of neutrophil elastase on the severity of SMRI in a rat model.