过氧化体增殖物激活型受体γ对肥厚心肌炎症反应的调控(英文)

Peroxisome proliferator-activated receptor-gamma in the regulation of inflammatory reaction in rats with myocardial hypertrophy

背景:过氧化体增殖物激活型受体γ可以通过抑制白细胞介素6、环氧合酶、内皮素1、一氧化氮合酶、基质金属蛋白酶9、明胶酶、黏附分子等的表达,抑制心肌肥厚中炎性反应。目的:观察压力负荷所致心肌肥厚过程中,过氧化体增殖物激活型受体γ配体-罗格列酮钠对肥厚心肌中炎性因子的影响。设计:随机对照动物实验。单位:解放军第三军医大学新桥医院心血管外科。材料:纯种S.P.F.级雄性SD大鼠50只,体质量(220±22)g。方法:实验于2004-08/2005-10在解放军第三军医大学野战外科研究所完成。SD大鼠50只随机分为对照组、假手术-生理盐水组、假手术-罗格列酮组、心肌肥厚-生理盐水组、心肌肥厚-罗格列酮组,各10只。采用腹主动脉缩窄法复制压力超负荷大鼠心肌肥厚模型,罗格列酮组:于术后4周用罗格列酮钠生理盐水溶液4mg/(kg·d)腹腔注射1周;生理盐水组:于术后4周用生理盐水腹腔注射1周[1mL/(kg·d)]。术后5周测定心肌肥厚指数及血液动力学指标;放免法检测左心室肌肿瘤坏死因子α、血小板活化因子含量,以及髓过氧化物酶含量;逆转录聚合酶链反应法检测心肌中过氧化体增殖物激活型受体γmRNA的表达;EMSA法检测核因子κB活性。主要观察指标:动物模型大鼠血流动力学和心室重塑指标,心肌炎性指标检测。结果:实验动物50只,对照组中1只在饲养3周后因撕咬外伤造成死亡,49只进入结果分析。①在主动脉缩窄术后心肌肥厚-罗格列酮组肥厚心肌中瘤坏死因子α、血小板活化因子、髓过氧化物酶的含量比心肌肥厚-生理盐水组显著降低(P<0.01～0.05),但仍高于对照组水平(P<0.01)。②心肌肥厚-罗格列酮组、心肌肥厚-生理盐水组心肌组织中过氧化体增殖物激活型受体γmRNA表达均明显高于对照组(P<0.01),且心肌肥厚-罗格列酮组高于心肌肥厚-生理盐水组(P<0.01)。③心肌肥厚-生理盐水组、心肌肥厚-罗格列酮组心肌细胞核因子κB的DNA结合活性明显高于对照组(P<0.01),且心肌肥厚-罗格列酮组明显低于心肌肥厚-生理盐水组(P<0.01)。结论:压力负荷增加引起心肌肥厚,肥厚心肌组织中核因子-κB激活明显增强,肿瘤坏死因子α、PAF、髓过氧化物酶表达升高,这一炎症反应能被过氧化体增殖物激活型受体γ人工合成配体罗格列酮钠所抑制。

BACKGROUND： Peroxisome proliferator-activated receptor-gamma （PpAR-γ） can restrain the inflammatory reaction of hypertrophic myocardium through restraining the expression of interleukin-6, cyclooxygenase, en dothelin-1, nitricoxide synthase, matrix metalloproteinase-9, gelatinase and adhesion molecule, etc. OBJECTIVE： To observe the influence of rosiglitazone sodium（the ligand for PPAR-γ） on inflammatory factors in rats with myocardial hypertrophy in the course of myocardial hypertrophy resulting from pressure load. DESIGN： Randomized controlled trial based on animals. SETTING： Department of Cardiovascular Surgery, Xinqiao Affiliated Haspital, the Third Military Medical University of Chinese PLA. MATERIALS： Fifty purebred male SD rats of S.P.F. grade, whose body mass was （220±22） g. METHODS： The experiment was completed in the Institute of Battle Surgical Research, the Third Military Medical University of Chinese PLA from August 2004 to October 2005. Fifty rats were randomly divided into 5 groups： control group, sham operation-normal saline group, sham operationrosiglitazone group, myocardial hypertrophy-normal saline group and myocardial hypertrophy-rosiglitazone group, 10 rats per group. The rat model of myocardial hypertrophy induced by pressure overload was established with the method of coarctation of abdominal aorta. Rosiglitazone group： At the postoperative 4^th week, the rats were injected intraperitoneally with the normal saline solution of rosiglitazone sodium [4 mg/（kg.d）] for 1 week. Normal saline group： At the postoperative 4^th week, the rats were injected intraperitoneally with normal saline[1 mL/（kg.d）] for 1 week. At the postoperative 5^th week, the indexes of myocardial hypertrophy and hemodynamics were determined. The contents of tumor necrosis factor-α, platelet activating factor and myeloperoxidase in the left ventricle muscle were determined with radioimmunosorbent technique. The expression of PPAR-γ mRNA was detected with RT-polymerase chain reaction. The activity of nuclear factor-kB was detected with EMSA. MAIN OUTCOME MEASURES： The indexes of hemodynamics, cardiac ventricle reconstitution and cardiac muscle in the rat models. RESULTS： Except 1 rat in the control group died of the external injury induced by biting after 3 weeks, 49 of 50 rats entered the result analysis.①Afier the coarctation of aorta, the contents of tumor necrosis factor- α, platelet activating factor and myeloperoxidase of hypertrophic myocardium in the myocardial hypertrophy-rosiglitazone group were lower significantly than those in the myocardial hypertrophy-normal-saline group（P 〈 0.01-0.05）, but they were still higher than those in the control group（P 〈 0.01）.②The expressions of PPAR-γ mRNA of myocardial tissue in both the myocardial hypertrophy-rosiglitazone and myocardial hypertrophy-normal saline groups were higher obviously than those in the control group（P 〈 0.01）, and those in the myocardial hypertrophy-rosiglitazone group were higher than those in the myocardial hypertrophy-normal saline group（P 〈 0.01）.①）The activity of nuclear factor-kB combined with DNA in cardiac muscle cell in both the myocardial hypertrophy-normal saline and myocardial hypertrophy-rosiglitazone groups were higher obviously than those in the control group （P 〈 0.01）, and those in the myocardial hypertrophy-rosiglitazone group were lower obviously than those in the myocardial hypertrophy-normal saline group（P 〈 0.01）. CONCLUSION： The increasing of pressure load induces myocardial hy-pertrophy. The activation of nuclear factor-kB in the tissue of hypertrophic myocardium is strengthened obviously. The expressions of tumor necrosis factor-a, platelet activating factor and myeloperoxidase in hypertrophic myocardium increase. This inflammatory reaction, which is strengthened obviously, can be restrained by rosiglitazone sodium that is the synthetical ligand for PPAR-γ.