蛋白酶体抑制剂MG-132对心肌梗死后心衰大鼠心功能及心肌肌钙蛋白Ⅰ的影响

Effects of proteasome inhibitor MG-132 on heart function and cardiac troponin Ⅰ in rats with chronic heart failure caused by myocardial infarction

目的探讨泛素蛋白酶体系统对心肌梗死后心衰大鼠心功能及心肌肌钙蛋白Ⅰ的影响。方法将制作成功的心肌梗死后心衰大鼠模型纳入研究,45只大鼠随机分为:①MG-132组:结扎左冠状动脉前降支,腹腔内注射MG-1320.1 mg/(kg.d)(溶于2 ml生理盐水);②心肌梗死(MI)组:结扎左冠状动脉前降支,腹腔内注射2 ml/d生理盐水;③假手术(Sham)组:手术过程同心肌梗死组,但只穿线通过左冠状动脉前降支不打结,腹腔内注射2 ml/d生理盐水。所有腹腔内注射持续7周后,检测各组大鼠心脏血流动力学及血清脑钠肽水平,电镜检测心肌肌小节结构变化,Real-time PCR及Western blot方法检测心肌cTnI的mRNA水平和蛋白质表达。结果与MI组相比,MG-132组大鼠心衰所致死亡率有降低趋势(0vs20%),LVPS及+dp/dtmax升高(分别为[85.69±14.65)vs(71.22±7.89)mmHg,P<0.05;(2 327.57±597.96)vs(1 047.20±168.65)mmHg/s,P<0.01],LVEDP下降[(16.85±2.05)vs(23.40±6.08)mmHg,P<0.01],NT-proBNP水平降低[(1 474.15±702.61)vs(3 920.56±1 919.04)pg/ml,P<0.001];MG-132还改善了肌小节结构,上调cTnI的mRNA及蛋白质表达[分别为(2.4±1.1)vs(0.6±0.2),P<0.01;(0.83±0.07)vs(0.63±0.10),P<0.05]。结论 MG-132改善了肌小节结构,与上调cTnI的mRNA及蛋白质表达有关。

Objective To investigate the effects of proteasome inhibitor MG-132 on the ubiquitin-proteasome system and on heart function and cardiac troponin Ⅰ（cTnI） in rats with chronic heart failure（CHF） caused by myocardial infarction（MI）.Methods Coronary artery ligation was used to build animal models of CHF.Forty-five adult Sprague-Dawley rats were randomly divided into 3 groups： MG-132 group,MI group,and Sham group.In the MG-132 group,the ligation of left anterior descending coronary arteries and the intraperitoneal injection of MG-132 [0.1 mg/（kg·d）,dissolved in 0.9% saline 2 ml] were performed.In the MI group,the ligation of left anterior descending coronary arteries and the intraperitoneal injection of saline（2 ml/d） were performed.In the Sham group,rats also underwent the intraperitoneal injection of saline（2 ml/d）,but threads were only passed through the left anterior descending coronary arteries without completing the ligation.After intraperitoneal injection in the three groups continually for 7 weeks,hemodynamics and serum B-type natriuretic peptide level were measured,sarcomere morphology change was measured by electronic microscopy,and the mRNA level and protein expression of myocardial cTnI were investigated by real-time PCR and Western blotting.Results The MG-132 group,compared with the MI group,demonstrated lower mortality（0 vs 20%）,higher systolic left ventricular pressure（LVPS）（85.69±14.65 mmHg vs 71.22±7.89 mmHg,P0.05） and ＋dp/dtmax（2 327.57±597.96 mmHg/s vs 1 047.20±168.65 mmHg/s,P0.001）,and lower left ventricular end-diastolic pressure（LVEDP）（16.85±2.05 mmHg vs 23.40±6.08 mmHg,P0.001） and NT-proBNP level（1 474.15±702.61 pg/ml vs 3 920.56±1 919.04 pg/ml,P0.001）.MG-132 improved the sarcomere morphology and upregulated the mRNA and protein expressions of myocardial cTnI（2.4±1.1 vs 0.6±0.2,P0.01;0.83±0.07 vs 0.63±0.10,P0.05）.Conclusion Our results demonstrate that inhibiting ubiquitin-proteasome system can improve the prognosis of CHF caused by myocardial infraction by decreasing the cTnI degradation.In addition,MG-132 can improve the sarcomere morphology,and this is associated with the upregulation of mRNA and protein expressions of myocardial cTnI.