甲状腺功能亢进性心肌病兔血管紧张素转换酶及血管紧张素Ⅱ型受体的表达

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

目的探讨甲状腺功能亢进性心肌病（甲亢性心肌病）的发病机制。方法将40只健康成年新西兰大白兔随机均分为空白对照组、L-甲状腺素（L-Thy）组、咪哒普利组和缬沙坦组4组。用L-Thy45μg·kg^-1·d^-1连续腹腔注射28d建立甲亢性心肌病动物模型。测定各组动物左右心室肥厚指数和心肌细胞直径；用Masson染色法测定胶原容积分数；用放射免疫法检测血浆及组织血管紧张素Ⅱ（AngⅡ）浓度；用逆转录-聚合酶链反应（RT—PCR）半定量法检测血管紧张素转换酶（ACE）、Ⅰ型血管紧张素Ⅱ受体（AT1R）、Ⅱ型血管紧张素Ⅱ受体（AT2R）的mRNA表达；用蛋白质免疫印迹法（Western blotting）检测ACE、AT1R、AT2R的蛋白表达。结果L—Thy可诱导心肌肥厚及心肌纤维化，使血浆与局部组织AngⅡ浓度升高，并可使ACE、AT1R、AT2R的mRNA及蛋白表达均上调（P均〈0．01）。咪哒普利和缬沙坦均可显著抑制L—Thy诱导的心肌肥厚和纤维化（P均〈0．05）；咪哒普利还可降低血浆与局部心肌组织AngⅡ水平（P均〈0．01），对AT1R、AT2R和ACE的mRNA和蛋白表达均无影响（P均〉0．05）；缬沙坦能显著升高血浆AngⅡ浓度（P〈0．01），但不升高组织AngⅡ浓度（P〉0．05），并能显著上调AT1R、AT2R的mRNA及蛋白表达（P均〈0．01），对ACE的mRNA和蛋白表达无影响（P均〉0．05）。结论肾素-血管紧张素系统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诱导的心室重构。

Objective To explore the pathogenesis of hyperthyroid cardiomyopathy. Methods A rabbit model of hyperthyroid cardiomyopath was reproduced by daily intraperitoneal injection of L - thyroxine （L-Thy, 45 μg · kg^-1· d^-1） for 28 consecutive days. Forty New Zealand rabbits were randomly divided into fours groups： control group, L -Thy group, imidapril group, and valsartan group. Ventricular tissues were harvested after 4 weeks. Cardiac hypertrophy index and cardiomyocyte diameter were assessed. Cardiac fibrosis was shown by Masson＇s stain and collagen volume fraction （CVF） was measured using pathological image analytic system. Plasma and cardiac angiotensin Ⅱ （Ang Ⅱ ） concentration were measured with radioimmunoassay （RIAs）. mRNA expression of angiotensin converting enzyme （ACE）, one tape angiotensin recipient - Ⅱ （AT1R） and AT2R were semi -quantified with reverse transcription -polymerase chain reaction （RT -PCR）. Expression of ACE, AT1R and AT2R protein were evaluated with Western blotting analysis. Results Compared with control group, rabbits treated with L - Thy only were found to have remarkable myocardial hypertrophy and extracellular matrix fibrosis. Increased plasma and tissue Ang 1 were detected in L - Thy group. RT - PCR and Western blotting analysis revealed enhanced mRNA and protein expression of ACE, AT1R and AT2R. It was also demonstrated that both imidapril and valsartan alleviated cardiac hypertrophy and extracellular matrix fibrosis induced by L - Thy. Compared with L - Thy and valsartan group, imidapril group showed significantly lower plasma /tissue Ang 1 concentration and more effective inhibition of extracellular matrix fibrosis. Imidapril did not alter the expression of ACE, AT1R or AT2R. Plasma concentration of Ang Ⅱ/ was markedly higher in valsartan group compared with L - Thy group, whereas tissue Ang Ⅱ concentration showed no significant difference between two groups. In valsartan group, AT1R and AT2R mRNA expressions were significantly upregulated, whereas valsartan did not change mRNA and protein expression of ACE. Conclusion Renin -angiotensia system （RAS） may play an important role in hyperthyroid cardiomyopathy. Imidapril and valsartan may exert benefical effects on hyperthyroid cardiomyopathy via retarding myocardial remodeling.