比格列酮和15d-PGJ_2抑制促炎细胞因子减轻自身免疫性心肌炎  

PPAR-γ ligands attenuate autoimmune myocarditis associated with inhibition the expression of inflammatory cytokines

作　　者：袁祖贻[1] 刘艳[1] 刘豫[1] 张继军[1] 岸本千晴[2] 王燕妮[1] 马爱群[1] 刘治全[1] 

机构地区：[1]西安交通大学第一医院心内科,710061 [2]日本京都大学附属病院循环科

出　　处：《中华心血管病杂志》2004年第12期1104-1108,共5页Chinese Journal of Cardiology

基　　金：国家自然科学基金资助项目(30170371)

摘　　要：目的 探讨过氧化物酶体增殖因子活化受体γ(PPARγ)在急性心肌炎发病中的作用;PPARγ配体治疗能否减轻心肌炎及其可能的机制。方法 6周龄雄性Lewis大鼠24只诱导自身免疫性心肌炎,随机分为阳性对照、15d-PGJ2治疗组及比格列酮治疗组(各组8只),正常大鼠8只作为正常对照。观察PPARγ配体15 d-PGJ2 注射(200 μg·kg-1·d-1)和比格列酮口服(10 mg·kg-1·d-1)治疗对心肌炎症程度的影响;免疫组化检测心肌PPARγ表达、免疫杂交检测IκBα、IL-1β和TNFα蛋白表达;核酸酶保护法检测心肌组织促炎细胞因子mRNA表达、电泳迁移率变动分析检测NF-κB的DNA结合活性。结果 ①PPARγ在炎症心肌组织中表达增强,主要定位在炎性浸润细胞的核和核周围区;②15d-PGJ2和比格列酮治疗使心肌炎症得到减轻,心重／体重、炎症分级严重程度明显减轻;③PPARγ配体15d-PGJ2和比格列酮治疗明显降低心肌组织中多种炎性细胞因子mRNA表达,及降低心肌内上调的IL-1β和TNFα蛋白表达;④与正常对照组相比,心肌炎阳性对照组心肌NF-κB的DNA结合活性增加5.6倍,15d-PGJ2和比格列酮治疗降低增强的NF-κB结合活性。⑤心肌炎阳性对照组心肌细胞核内NF-κB抑制物IκB蛋白含量明显降低;与心肌炎组相比,15d-PGJ2和比格列酮治疗分别增加IκB蛋白含量2.2?Objective Peroxisome proliferator-activated receptor-γ (PPAR-γ) activators have the anti-inflammatory effects. The present study was to test the hypothesis that activation of PPAR-γ reduced experimental autoimmune myocarditis (EAM) and was associated with suppression of the expression of proinflammatory cytokines. Methods EAM was induced in Lewis rats by immunization with porcine cardiac myosin. PPAR-γ ligands 15-deoxy-△12,14-PGJ2 (15d-PGJ2) 200 μg·kg-1·d-1 by i. p. and pioglitazone (PIO) 10 mg·kg-1·d-1 were administrated orally for 3 weeks in rats with EAM. The pathological change of myocarditis was determined. PPAR-γ expression was checked by immunohistochemistry; the myocardial IL-1β and TNFα protein expressions and mRNA expressions of inflammatory cytokines were evaluated by western blotting or by ribonuclease protection assay, NF-κB binding activity was determined by electrophoretic mobility shift assay. Results ①The enhanced PPAR-γexpression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. ② The severity of myocarditis in the rats administered with PPAR-γ ligands was markedly reduced demonstrated by improved heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores. ③ PPAR-γ ligands suppressed myocardial mRNA expressions of inflammatorycytokines, as well as the protein expressions of IL-1β and TNFα in rats with EAM. ④ There was a marked activation of NF-κB in the rats with myocarditis, which was inhibited in the rats of 15d-PGJ2-treated and PIO-treated groups.⑤A remarkable decrease of inhibitor (I) κB was found in the nuclear fractions from inflammatory myocardium, and the treatment of 15d-PGJ2 and PIO enhanced the levels of I κB. Conclusions PPAR-γmight have a role in the pathophysiology of EAM. PPAR-γ ligands could ameliorate EAM, which may be associated with suppression the expression of proinflammatory cytokines.

关 键 词：治疗 自身免疫性心肌炎 PPARΓ配体 促炎细胞因子 NF—κB 减轻 炎症 IΚBΑ 阳性对照 核酸酶 

分 类 号：R542.21[医药卫生—心血管疾病] R735.7[医药卫生—内科学]