高甲状腺素模型心室组织中血管紧张素转化酶及血管紧张受体的表达

Expression of angiotensin converting enzyme,angiotensin Ⅱ receptor 1,and angiotensin Ⅱ receptor 2 in rabbits with hyperthyroid cardiomyopathy

目的研究甲状腺功能亢进(简称甲亢)性心肌病兔心室组织血管紧张素转化酶(ACE)及血管紧张受体表达,探讨甲亢性心肌病的发病机制。方法健康成年新西兰大白兔40只,随机分为4组:对照组,左旋甲状腺素(L-thy)组,咪哒普利组(L-Thy+I midapril),缬沙坦组(L-Thy+Valsartan)。L-Thy[45μg/(kg.d)×28 d]腹腔注射建立甲亢动物模型,测定左右心室心肌肥厚指数、心肌细胞直径,Masson′s染色测定胶原容积分数,放免法检测血浆及组织血管紧张素Ⅱ(AngⅡ)浓度,RT-PCR半定量检测ACE、血管紧张素受体1(AT1R)、血管紧张素受体2(AT2R)mRNA表达,Western blot检测ACE、AT1R、AT2R蛋白表达。结果 L-Thy可诱导心肌肥厚及心肌纤维化,血浆与局部组织AngⅡ浓度升高,ACE mRNA及蛋白表达上调,AT1R、AT2R mR-NA及蛋白表达上调。咪哒普利和缬沙坦均可显著抑制L-Thy诱导的心肌细胞肥厚和纤维化,咪哒普利可降低血浆与局部心肌组织AngⅡ水平,对AT1R、AT2R和ACE的表达无影响。缬沙坦显著升高血浆AngⅡ浓度,但不升高组织AngⅡ浓度;且显著上调AT1R、AT2R mRNA表达,对ACE的表达无影响。结论甲亢性心肌病兔有循环和组织AngⅡ浓度升高,AT1R、AT2R和ACE表达上调,肾素-血管紧张素系统(RAS)可能参与甲亢性心肌病的发病机制。咪哒普利和缬沙坦可以改善L-Thy诱导的心肌重构。

Objective To study the expression of angiotensin converting enzyme（ACE）,angiotensin Ⅱ receptor 1（AT1R）,and angiotensin Ⅱ receptor 2（AT2R） in rabbits with hyperthyroid cardiomyopathy induced by levothyroxine（L-Thy）.Methods A rabbit model of hyperthyroidism was established by daily intraperitoneal injections of L-Thy（45μg/kg per day,28 d）.Forty New Zealand rabbits were randomly divided into fours groups：control group（n=10）,L-Thy group（L-Thy only,n=10）,imidapril group（L-Thy＋ imidapril,n=10）,and valsartan group（L-Thy＋valsartan,n=10）.Ventricular tissues were collected at 4 weeks.Cardiac hypertrophy index and cardiomyocyte diameter were detected.Cardiac fibrosis was displayed by Masson′s stain and collegen volume fraction（CVF）was measured using pathological image analytic system.Plasm and cardiac angiotensin Ⅱ concentration were measured with radioimmunoassays（RIAs）.mRNA expression of ACE,AT1R,and AT2R were semi-quantified with RT-PCR.Expression of ACE,AT1R,and AT2R protein was evaluated with Western blot analysis.Results Compared with control group,rabbits merely treated with L-Thy displayed remarkable myocardial hypertrophy and extracellular matrix fibrosis.Increased plasm and tissue AngⅡ was detected in L-Thy group.RT-PCR and Western blot analysis revealed enhanced mRNA and protein expression of ACE,AT1R,and AT2R.Our study demonstrated that both imidapril and valsartan alleviated cardiomyocyte hypertrophy and extracellular matrix fibrosis induced by L-Thy.Compared with L-Thy and valsartan group,imidapril group showed significantly lower plasm /tissue AngⅡ concentration and more effective inhibition of extracellular matrix fibrosis.Imidapril did not alter expression of ACE,AT1R,and AT2R.Plasm concentration of AngⅡ was markedly higher in valsartan group compared with L-Thy group,whereas tissue AngⅡ concentration was not significantly different between the two groups.In valsartan group,AT1R and AT2R mRNA expressions were significantly upregulated,whereas valsartan did not change expression of ACE.Conclusion Expression of ACE,AT1R,and AT2R is upregulated in rabbits with hyperthyroid cardiomyopathy induced by L-Thy.Renin-angiotension system（RAS）may play important role in hyperthyroid cardiomyopathy.Imidapril and valsartan may exert benefical effects on hyperthyroid cardiomyopathy via improring myocardial remodeling.