硫化氢下调STAT3改善MMPs/TIMPs失调及高甲状腺素诱导的心肌纤维化  

Improvement of hydrogen sulfide on the disorder of MMPs/TIMPs and myocardial fibrosis induced by high thyroxine through downregulating STAT3

作　　者：龙俊蓉 刘盛权 唐芬[1] 谭文婷[1] 刘茂军[1] 梁彪[1] 李子宁[1] 褚春 杨军[1] LONG Jun-rong;LIU Sheng-quan;TANG Feng;TAN Wen-ting;LIU Mao-jun;LIANG Biao;LI Zi-ning;CHU Chun;YANG Jun(Department of Cardiology, First Affiliated Hospital of University of South China, Hunan Hengyang 421001, China;Department of Pharmacy, Second Affiliated Hospital of University of South China, Hunan Hengyang 421001, China)

机构地区：[1]南华大学附属第一医院心血管内科,湖南衡阳421001 [2]南华大学附属第二医院药剂科,湖南衡阳421001

出　　处：《中国医院药学杂志》2018年第7期697-700,707,共5页Chinese Journal of Hospital Pharmacy

基　　金：国家自然科学基金(编号:81202830);湖南省自然科学基金(编号:2017JJ3278)

摘　　要：目的:观察外源性硫化氢(hydrogen sulfide,H2S)对高甲状腺素诱导下的大鼠心肌纤维化的作用,及其对MMPs/TIMPs和STAT3蛋白表达的影响。方法 :随机将40只雄性SD大鼠分成4组,分别为对照组(Con)、甲亢组(L-Thy)、硫化氢干预组(L-Thy+H2S)及硫化氢对照组(H2S)。以左旋甲状腺素10 m L·(kg·d)-1腹腔注射制备甲亢大鼠模型,L-Thy+H2S组及H2S组同时给予硫氢化钠溶液1 m L·(kg·d)-1腹腔注射,Con组及L-Thy组则以等量生理盐水代替。4周后处死大鼠,Masson染色观察左室心肌组织胶原沉积,并计算胶原容积分数(collagen volume fraction,CVF);以Western-blot法检测基质金属蛋白酶8(matrix metalloproteinases 8,MMP8)、MMP16、基质金属蛋白酶组织抑制物1(tissue inhibitors of metalloproteinases 1,TIMP1)和信号转导子和转录激活子3(signal transducer and activator of transcription 3,STAT3)蛋白的表达。结果:与Con组相比,L-Thy组心肌组织间胶原沉积明显增多,且CVF增加(P<0.05);而且MMP8、MMP16及STAT3蛋白表达上升(P<0.05),TIMP1蛋白表达明显下降。L-Thy+H2S组与L-Thy组相比,大鼠心肌组织胶原纤维沉积减少,CVF降低(P<0.05);且MMP8、MMP16以及STAT3蛋白表达减少,TIMP1表达明显增加(P<0.05)。结论:硫化氢可能通过下调STAT3改善MMPs/TIMPs失调,从而改善高甲状腺素诱导的心肌纤维化。OBJECTIVE To observe the effects of exogenous hydrogen sulfide（ H2 S） on myocardial fibrosis induced by high dose thyroxine and the expression of MMPs/TIMPs and STAT3. METHODS Forty male SD rats were divided into four groups by a completely randomized method： control group（ Con）,hyperthyroidism group（ L-Thy）,hydrogen sulfide intervention group（ L-Thy ＋H2 S） and hydrogen sulfide control group（ H2 S）. A rat model of hyperthyroidism was established by intraperitoneal injection of levothyrocine（ L-Thy,10 m L·kg^-1·d^-1. Then,animals in L-Thy ＋ H2 S group and H2 S group were treated with sodium hydrosulfide solution（ 1 ml·kg^-1·d^-1,animals in Con group and L-Thy group were treated with the same volume of saline. These rats were sacrificed after four weeks,the collagen deposition of left ventricular myocardium was observed by Masson staining,the collagen volume fraction（ CVF） was calculated,and the expressions of MMP8,MMP16,TIMP1 and STAT3 proteins were detected by Western-blot. RESULTS Compared with Con group,the L-Thy group showed significantly increased collagen fibers,the CVF also had increased collagen fibers（ P〈0. 05）. Besides,the MMP8,MMP16 and STAT3 showed increased protein expression,while TIMP1 protein expression decreased significantly（ P〈0. 05）. Compared with L-Thy group,the deposition of collagen fibers in H2 S ＋ L-Thy group was improved,and CVF decreased（ P〈0. 05）. In addition,the expressions of MMP8,MMP16 and STAT3 proteins decreased,TIMP1 expression obviously increased（ P〈0. 05）. CONCLUSION Hydrogen sulfide may improve the expression disorder of MMPs/TIMPs by downregulating STAT3,thereby improving the high dose thyroxine induced myocardial fibrosis.

关 键 词：甲状腺功能亢进 硫化氢 心肌纤维化 STAT3 MMPS/TIMPS 

分 类 号：R969[医药卫生—药理学]