Abstract
Background. Myocardial ischemial reperfusion represents a clinically relevant problem associated with thrombolysis, angioplasty, and coronary bypass surgery. Injury of myocardium due to ischemial reperfusion includes cardiac contractile dysfunction, arrhythmias, and irreversible myocytes damage. These changes are considered to be the consequence of imbalance between the formation of oxidants and the availability of endogenous antioxidants in the heart. Objective. This study was undertaken to investigate the potential role of Simvastatin in the amelioration of myocardial I/R injury induced by ligation of coronary artery in a rat model. Materials and Methods. Adult male Swiss Albino rats were randomized into 4 equal groups. Group (1): sham group: rats underwent the same anesthetic and surgical procedures as those in the control group except ligation of LAD coronary artery, group (2): control group: rats were subjected to regional ischemia for 25 min and reperfusion for 2 hours by ligation of LAD coronary artery, group (3): control vehicle group: rats received vehicle of Simvastatin (normal saline) via IP injection and were subjected to regional ischemia for 25 min and reperfusion for 2 hours by ligation of LAD coronary artery, group (4): Simvastatin treated group: rats were pretreated with Simvastatin 1 mg/kg i.p. 1 hr before ligation of LAD coronary artery. At the end of experiment (2 hr of reperfusion), blood samples were collected from the heart for the measurement of plasma level of cardiac troponin I (cTnI). After that the heart was harvested and divided into 3 parts; one part was used for measurement of apoptosis, another part was homogenized for the measurement of tissue tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α, and the last part for histopathology study. Results. Compared with the sham group, levels of myocardial TNF-α and IL-1β, IL-6, MCP-1, and MIP-1α and plasma cTnI were increased (P < 0.05). Histologically, all rats in control group showed significant (P < 0.05) cardiac injury. Furthermore, all rats in control group showed significant (P < 0.05) apoptosis. Simvastatin significantly counteracted the increase in myocardium level of TNF-α, IL-1B, IL-6, MCP-1 and MIP-1α, plasma cTnI, and apoptosis (P < 0.05). Histological analysis revealed that Simvastatin markedly reduced (P < 0.05) the severity of heart injury in the rats that underwent LAD ligation procedure. Conclusions. The results of the present study reveal that Simvastatin may ameliorate myocardial I/R injury in rats via interfering with inflammatory reactions and apoptosis which were induced by I/R injury.
Highlights
Ischemia/reperfusion injury describes the experimentally and clinically prevalent finding that tissue ischemia with inadequate oxygen followed by successful reperfusion initiates a wide and complex array of inflammatory responses that may aggravate local injury as well as induce impairment of remote organ function [1]
The damage is mediated by various cytokines, chemokines, adhesion molecules, and compounds of the extracellular matrix. The expression of these factors is regulated by specific transcription factor with NF-kB being one of the key modulators of inflammation [5]. Apoptosis is another mechanism of myocardial injury associated with ischemial reperfusion injury; it seems that apoptotic cell death in the myocardium is initiated during ischemia, but the energy needed for the execution is provided during reperfusion [6]
In the Simvastatin treatment group, myocardium levels of tumor necrosis factor-α (TNF-α), IL-1B, and IL-6 were reduced significantly compared with the control group (P < 0.05)
Summary
Ischemia/reperfusion injury describes the experimentally and clinically prevalent finding that tissue ischemia with inadequate oxygen followed by successful reperfusion initiates a wide and complex array of inflammatory responses that may aggravate local injury as well as induce impairment of remote organ function [1]. Ischemial reperfusion injury prompts a release of oxygen free radicals, cytokines, and other proinflammatory mediators that activate both the neutrophils and the coronary vascular endothelium Activation of these cell types promotes the expression of adhesion molecules on both the neutrophils and endothelium, ISRN Pharmacology which recruits neutrophils to the surface of the endothelium and initiates a specific cascade of cell-cell interactions, leading first to adherence of neutrophils to the vascular endothelium, followed later by transendothelial migration and direct interaction with myocytes. This specific series of events is a prerequisite to the phenotypic expression of reperfusion injury, including endothelial dysfunction, microvascular collapse and blood flow defects, myocardial infarction, and apoptosis [3]. The results of the present study reveal that Simvastatin may ameliorate myocardial I/R injury in rats via interfering with inflammatory reactions and apoptosis which were induced by I/R injury
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