替米沙坦对腹主动脉缩窄大鼠内质网应激相关的心肌细胞凋亡的影响

Effects of telmisartan on endoplasmic reticulum stress induced cardiomyocyte apoptosis in abdominal aortic banded rats

目的探讨血管紧张素Ⅱ受体拮抗剂替米沙坦对腹主动脉缩窄术后大鼠内质网应激相关的心肌细胞凋亡的影响。方法30只雄性SD大鼠随机分为假手术组（n=10），腹主动脉缩窄组（n=10），腹主动脉缩窄＋替米沙坦组（n=10）。术后10周各组大鼠用导管法测量血液动力学指标并留取心肌标本测左心室质量指数，心肌细胞凋亡用TUNEL法检测，心肌内质网应激信号通路分子GRP78、CHOP用免疫印迹法和免疫组化法检测。结果（1）腹主动脉缩窄组左心室质量指数（3．29±0．19）mg／g明显高于假手术组（2．17±0．22）mg／g（P〈0．01），左心室舒张末压（9．71±0．52）mmHg（1mmHg=0．133kPa）亦明显高于假手术组（2．79±0．13）mmHg，左心室收缩末压（105．61±6．66）mmHg明显低于假手术组（135．02±5．95）mmHg（P〈0．01），而腹主动脉缩窄＋替米沙坦组上述指标分别为（2．34±0．08）mg／g、（4．70±0．36）mmHg、（127．62±4．99）mmHg，明显优于腹主动脉缩窄组（P〈0．01）。（2）腹主动脉缩窄＋替米沙坦组心肌细胞凋亡指数（13．42±0．74）％显著低于腹主动脉缩窄组（35．51±0．65）％（P〈0．01）。（3）腹主动脉缩窄组内质网应激信号分子GRP78、CHOP蛋白表达RCRP78/β-actin0．436±0．007、RCHOP／β-actin 0．747±0．034显著高于假手术组RCRP78/β-actin 0．144±0．009、RCHOP／β-actin 0．316±0．007（P〈0．01），而腹主动脉缩窄＋替米沙坦组GRP78、CHOP（RGRP78/β-actia 0．213±0．007、RCHOP/β-actin 0．451±0．019），明显低于腹主动脉缩窄组（P〈0．01）。结论内质网应激参与了腹主动脉缩窄术后大鼠心肌细胞凋亡，替米沙坦对内质网应激相关的心肌细胞凋亡有保护作用。

Objective To investigate the effects of telmisartan on endoplasm reticulum （ER） stress signal pathways and cardiomyocyte apoptosis in abdominal aortic banded rats. Methods Male SD rats were randomly divided into sham-operated group, abdominal aortic banding group （AAB） and AAB ＋ telmisartan （5 mg · kg^-1 · d^-1 per gavage, beginning at 1 week before AAB for 8 weeks, n = 10 each）. Ten weeks post AAB, hemodynamic measurements were performed, whole heart and left ventricular weights were obtained, cardiomyocyte apoptosis was measured by TUNEL method. Myocardial GRP78 and CHOP protein expresssions were detected by Western blot and immunohistochemistry. Results The ratio of left ventricular weight to body weight, the ratio of heart weight to body weight, left ventricular end diastolic pressure and the apoptosis index were significantly increased while left ventricular end systolic pressure and ＋ dp/dtmax were significantly decreased in AAB group than those in sham-operated group （ all P 〈 0.01 ）, these changes could be significantly attenuated by telmisartan （all P 〈 0. 01 ）. Moreover, myocardial GRP78 and CHOP expressions were significantly upregulated in AAB group than those in sham-operated group and telmisartan could significantly downregulate the increased GRF78, CHOP expressions （all P 〈 0.01 ）. Conclusions Increased ER stress might be responsible for enhanced cardiomyocyte apoptosis in AAB rats. Tetmisartan effectively attenuated the cardiomyocyte apoptosis and cardiac hypertrophy in AAB rats possibly through reducing ER stress.