| Objective: Coronary heart disease(coronary atherosclerotic heart disease, CHD) affect the quality of human life and health worldwide. In the past 30 years, the breakthrough and application in interventional cardiology greatly improve the treatment of CHD. Restoring blood flow is indispensable for rescuing the ischemic myocardium, but myocardial revascularization also suffers adverse damage known as myocardial ischemia/reperfusion(MI/R) injury. MI/R, which could increase the cardiac disorder of hemodynamics, not only damage the patient with revascularization, but also eventually lead to death. As the current commonly used drugs of therapy atherosclerosis(AS) and acute coronary syndrome(ACS), statins, in addition to regulation the lipid metabolism, also have the multiple pharmacological effects, involving stability of atherosclerotic plaque, improving endothelial function, and immune regulation. Based on such pharmacological effects, the treatment of statins in cardiovascular disease deserves further exploration. This study aimed at analysis the relationship between inflammatory and apoptosis of myocardial cells with MI/R injury in mice, and further investigated the direct effect and potential mechanism of statins decrease MI/R injury. Our study chose a new generation statins named rosuvastatin as representative. Meanwhile, this study detected inflammatory cytokines with different therapeutic dose of rosuvastatin, and further illustrated that dose and frequency of statins may influence anti-inflammatory and protection in MI/R injury. Our study expected to provide the more significance data for the clinical treatment strategy in patients with coronary heart disease.Methods: 1. One hundred and twenty male C57BL/6 mice were randomly divided into 3 groups: normal control group(Sham group), ischemia/reperfusion group(MI/R group), rosuvastatin pretreatment group(MI/R+R group), 40 mice in each group. In MI/R+R group, the mice were given 5 mg/kg rosuvastatin daily, for seven days in a row before the operation began. Sham group and MI/R group were given physiological saline, dosage and method according with the MI/R+R group. Mouse MI/R model was established. At MI/R 1 h, the plasma high sensitivity C-reactive protein(hs-CRP) and tumor necrosis factor(TNF-α) concentrations were detected by ELISA. At MI/R 3 h, myocardial apoptosis were observed by TUNEL stained and caspase-3 activity detection. At MI/R 24 h, mice myocardial tissue samples from 3 groups were stained by Evans blue/TTC staining to detect the myocardial infarction size.2. Sixty male C57BL/6 mice were randomly divided into 5 groups, namely sham operation group(Sham group), ischemia/reperfusion group(MI/R group), ischemia/reperfusion + normal dose group(MI/R+R group), ischemia/reperfusion + single loading dose group(MI/R+SL), and ischemia/reperfusion + repeated loading dose group(MI/R+ML). MI/R +R group were given 5 mg/kg rosuvastatin daily, for 7 consecutive days before the operation began; MI/R +SL group were given 20 mg/kg rosuvastatin, at 8 h before operation; MI/R + ML group were given 20 mg/kg rosuvastatin daily, for 7 consecutive days before the operation began; Sham group and MI/R group were given normal saline, dosage and method according with MI/R+R group. During MI/R 1 h, 3 h, 8 h, 24 h, 3d, and 7d, plasma hs-CRP and TNF-α concentration were detected by ELISA.Results: 1. The levels of plasma hs-CRP and TNF-α were higher in MI/R+R group and MI/R than those in Sham group(P <0.05), but the levels of plasma hs-CRP(0.64±0.23 mg/L vs. 1.51±0.24 mg/L,P <0.05)and TNF-α(137.40±3.64pg/ml vs. 161.55±8.05pg/ml,P <0.05)in group of MI/R+R were significantly lower than those in group MI/R.2. The positive rates of TUNEL stained and Caspase-3 activity were higher in groups of MI/R+R and MI/R than those in Sham group(P <0.05), but the positive rates of TUNEL stained and Caspase-3 activity in group of MI/R+R were significantly lower than that of MI/R group(P <0.05).3. The total ischemic area(AAR/LV×100%) were significantly higher in groups of MI/R+R and MI/R than those in Sham group(P <0.05). Meanwhile, there was no significant difference in total ischemic area between MI/R+R group and MI/R group. But in MI/R+R group, the myocardial infarction area(inf/AAR×100%) was significantly lower than that in MI/R group(P <0.05).4. At MI/R 1 h, 3 h, 8 h, and 24 h, the levels of plasma hs-CRP and TNF-α were significantly decreased in groups of MI/R, MI/R +R, MI/R +SL, and MI/R + ML, than those in MI/R group(P <0.05). At MI/R 1 h, 3 h, and 8 h, the levels of plasma hs-CRP and TNF-α were significantly lower in groups of MI/R+SL and MI/R+ML, than those in group of MI/R+R(P <0.05). At MI/R 24 h, there was no statistical difference in levels of plasma hs-CRP and TNF-α between groups of MI/R+R, MI/R+SL, and MI/R+ML. At MI/R 3 d, the levels of plasma hs-CRP and TNF-α in groups of MI/R and MI/R+R were higher than those in Sham group(P <0.05), whereas there was no statistical difference among groups of Sham, MI/R+SL, and MI/R+ML. But the levels of plasma hs-CRP and TNF-α in groups of MI/R+SL and MI/R + ML were still lower than those in MI/R group(P <0.05). At MI/R 7d, plasma hs-CRP and TNF-α levels were not found statistical difference each group.5. During the whole process of dynamic detections(at 1 h, 3 h, 8 h, 24 h, 3d and 7d), always there was no significant difference in levels of plasma hs-CRP and TNF-α between MI/R+SL group and MI/R+ML group.Conclusion: 1. Rosuvastatin pretreatment can significantly reduce inflammatory factor of hs-CRP and TNF-α, and then inhibit MI/R inflammatory and decrease MI/R injury in mice. When suffering myocardial infarction, rosuvastatin pretreatment can reduce the myocardial infarction area, and inhibit apoptosis of the myocardial cells significantly. The mechanism of statins reducing MI/R injury may involve its effect of anti-inflammatory and inhibition apoptotic. In addition, the mechanism of statins reducing the myocardial cell apoptosis may directly originate from its anti-inflammatory.2. Statin pretreatment can effectively reduce inflammation in MI/R injury. Compared with the commonly dosage, loading therapeutic dose of statins can greater reduce levels of hs-CRP and TNF-α, and inhibit MI/R inflammatory damage significantly, especially in MI/R injury early stage. In contrast, there was no significantly different in anti-inflammatory between two types of administration doze of statins, one of which was preoperative loading dose once and another was continuously loading dose. Administration of statins for continuously loading not showed better effect against inflammatory in MI/R injury. Based on economy, convenience and safety of statin treatment, the preoperative single loading dose of statin would be more conducive to the clinical treatment strategies in MI/R injury. |
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