硫化氢抑制p38MAPK和NF-κBp65信号通路活性改善糖尿病心肌纤维化的作用和机制  

Effects and mechanisms of exogenous hydrogen sulf ide on inhibiting the activation of p38MAPK/NF-kB p65 pathway to improve diabetic myocardial fibrosis

作　　者：宋冰 丁利 

机构地区：[1]锦州医科大学附属第一医院内分泌科,辽宁锦州121001 [2]锦州医科大学研究生学院,辽宁锦州121001

出　　处：《解放军医学杂志》2016年第11期902-908,共7页Medical Journal of Chinese People's Liberation Army

基　　金：辽宁省博士科研启动基金(20131067);辽宁省自然科学基金(201602308)~~

摘　　要：目的研究外源性硫化氢(H2S)对糖尿病心肌病小鼠心肌纤维化的改善作用及其机制。方法 24只雄性C57BL/6J小鼠随机分为正常对照组(NC组)、糖尿病对照组(ALX组)、低剂量Na HS治疗组(ALX+LDNa HS组)、高剂量Na HS治疗组(ALX+HDNa HS组),每组6只。采用四氧嘧啶(ALX)200mg/kg腹腔注射建立糖尿病小鼠模型,造模成功后,NC组和ALX组每天自由饮用自来水,ALX+LDNa HS组和ALX+HDNa HS组自由饮用浓度分别为30μmol/L和90μmol/L的Na HS(H2S供体)溶液。喂养8周后取材,采用HE染色观察心肌组织形态学变化,Real-time PCR检测p38丝裂原活化蛋白激酶(p38MAPK)、核转录因子-κB p65(NF-κB p65)m RNA的表达,Western blotting检测p-p38MAPK、p-NF-κB p65和Ⅰ型胶原蛋白的表达。结果与NC组比较,ALX组心肌组织胶原表达量增加,心肌间质出现纤维化,p38MAPK、NF-κB p65 m RNA表达明显增加(P<0.01),同时p-p38MAPK、p-NF-κB p65和Ⅰ型胶原蛋白表达也明显增高(P<0.01)。经硫化氢干预后糖尿病小鼠心肌纤维平行排列,心肌组织胶原表达量明显减少,心肌间质有少量结缔组织;p38MAPK、NF-κB p65 m RNA表达明显减少(P<0.01),p-p38MAPK、p-NF-κB p65和Ⅰ型胶原蛋白表达明显下降(P<0.01),且ALX+HDNa HS组较ALX+LDNa HS组明显改善(P<0.05)。结论 H2S可改善糖尿病小鼠心肌纤维化,可能与调节p38MAPK和NF-κB p65介导的炎症反应有关。Objective To study the effects of exogenous hydrogen sulfide （H2S） on myocardial fibrosis of diabetic mice and the mechanism thereof. Methods Twenty-four male adult C57BL/6J mice were randomly divided into 4 groups （6 each）： normal control group （NC group）, diabetes mellitus group （ALX group）, diabetes mellitus treated with low dose NariS group （ALX＋LDNaHS group） and diabetes mellitus treated with high dose Naris group （ALX＋HDNaHS group）. The diabetic mouse model was established by intraperitoneal injection of alloxan at 200mg/kg. Mice in NC group and ALX group drank tap water freely everyday, and in ALX＋LDNaHS group and ALX＋HDNaHS group were provided with sodium hydrosulfide （NariS, donor of HzS, 30}xmol/L and 90p^mol/L, respectively） in drinking water, and the histological specimens of mice were examined 8 weeks later. The morphological changes of cardiac tissue were examined with HE staining. The expressions of mRNA of p38mitogen-activated protein kinase （p38MAPK） and nuclear transcription factor kappa B p65 （NF-gB p65） were detected by ReaI-time PCR, and the expressions of p-p38MAPK, p-NF-KB p65 and Collagen I proteins were detected by Western blotting. Results Compared with NC group, the expression of collagen increased and there was fibrillation in the myocardial matrix, the expressions of mRNA of p38MAPK and NF-KB p65 increased obviously （P〈0.01）, the protein expressions of p-p38MAPK, p-NF-~B p65 and Collagen I increased significantly （P〈0.01） in ALX group; after intervention of H2S, the cardiac muscle fibers were parallel arranged, the expression of collagen was visibly decreased and there was less fibrillation in the myocardial matrix, the expressions of mRNA of p38MAPK and NF-KB p65 were obviously decreased （P〈0.01）, the protein expressions of p-p38MAPK, p-NF-KB p65 and Collagen I were significantly decreased （P〈0.01）, and more improvement was observed in ALX＋HDNAHS group than in ALX＋LDNAHS group （P〈0.05）. Conclusion H2S can

关 键 词：硫化氢 糖尿病心肌病 P38丝裂原活化蛋白激酶类 NF-KB P65 胶原I型 

分 类 号：R587.23[医药卫生—内分泌]