慢性心房颤动犬心房组织肾素血管紧张素系统激活与整合素β_1基因表达的意义

Effect of captopril on the gene expression of atrial integrin β_1 and renin angiotensin system activation in the chronic atrial fibrillation dog model

目的探讨慢性心房颤动(房颤)实验犬心房组织肾素血管紧张素系统(RAS)激活与整合素β1基因表达变化的意义及卡托普利的干预作用。方法健康杂种犬26只,随机分为3组,起搏组(n=11)及治疗组(n=9)均植入高频率心脏起搏器(400次/min),快速起搏犬右心耳8周,治疗组于起搏器植入前3d至起搏8周,每日给予卡托普利50mg,每日两次,口服。起搏8周后处死动物,分别于左、右心房、心耳取材,测定心房组织血管紧张素Ⅱ(AngⅡ)含量及心房组织整合素β1基因表达变化。对照组(n=6)未植入起搏器,与起搏、治疗组同步行相应检查。结果与对照组比较,起搏组左、右心房心肌AngⅡ浓度显著升高(左心房12.46±2.64对9.88±1.61;右心房11.38±3.77对7.49±1.65,P<0.05)。而治疗组起搏8周后,左、右心房心肌AngⅡ浓度与对照组比较差异无统计学意义,明显低于起搏组(左心房9.68±1.82对12.64±2.64;右心房7.12±1.01对11.38±3.77,P<0.05);与对照组比较,起搏组8周后,左心房整合素β1mRNA转录水平升高达95.35%(0.84±0.33对0.43±0.02,P<0.01),右心房整合素β1mRNA转录水平无显著变化(0.34±0.09对0.35±0.02,P>0.05)。治疗组起搏8周后,左心房整合素β1mRNA转录水平明显降低,低于起搏组(0.27±0.03对0.84±0.33,P<0.01)及对照组(0.27±0.03对0.43±0.02,P<0.01)。对照组及起搏组左心房整合素β1mRNA转录水平显著高于右心房,但右心房整合素β1mRNA转录水平3组之间比较差异无统计学意义。结论(1)长期快速起搏实验犬心房组织AngⅡ含量增高,整合素β1基因表达明显增高;(2)卡托普利可抑制慢性房颤实验犬心房组织RAS激活,抑制整合素β1基因表达。

Objective To investigate the renin angiotensin system （RAS） activation and gene expression of atrial integrin β in the chronic atrial fibrillation（AF） dog model and the effects of captopril in the treatment of AF. Methods Twenty-six mongrel dogs were randomly assigned to 3 groups ： pacing group （ n= 11 ）, treating group（ n = 9） and control group （ n = 6）. High frequency pacing （400 bpm） of the right atrial appendage was performed for 8 weeks in both the pacing group and treating group with permanent pacemaker. Pacing was not performed in the control group. In the treating group, all the dogs were given oral captopril 50 mg twice a day from 3 days before pacing to 8 weeks after pacing. Tissue samples were obtained from the atrial appendages and both the left and right atria when dogs were killed. Then the level of angiotensin Ⅱ （ Ang Ⅱ ） and gene expression of atrial integrin β1 in the tissue samples were assayed by radio-immunity and RT-PCR. Results Level of Ang Ⅱ was significantly higher in the pacing group than it in the control group （left atrium ：12. 46 ± 2. 64 vs 9. 88 ± 1.61 ; right atrium ： 11.38 ± 3.77 vs 7.49 ± 1.65, P 〈0. 05 ）. But the level of Ang Ⅱ in the treating group was no difference compared with it in the control group. However, the level of Ang Ⅱ in the treating group was markedly lower than it in the pacing group（ left atrium：9. 68 ± 1. 82 vs 12. 64 ±2. 64;right atrium：7. 12± 1.01 vs 11.38 ±3.77,P〈0. 05）. The expression level of mRNA of the left atrial integrin β1 in pacing group was significantly higher than it in the control group（0. 8g ±0. 33 vs 0. 43 ±0. 02,P 〈0. 01 ）. While there was no difference in the expression level of mRNA of the right atrial integrin β1 between the pacing group and the control group（0. 34 ± 0. 09 vs 0. 35 ± 0. 02, P 〉 0. 05 ）. The level of mRNA of the left atrium in the treating group was markedly lower than it in the pacing group （0. 27 ± 0. 03 vs 0. 84 ± 0. 33, P 〈 0. 001 ） and the control group （0. 27 ± 0. 03 vs 0. 43 ± 0. 02, P 〈 0. 001 ）. Level of mRNA of the left atrium was significantly higher than it of the right atrium in both the control group and the pacing group. However,there was no difference in the level of mRNA of the right atrium among all the 3 groups. Conclusions （ 1 ） Chronic high frequency pacing could significantly increase the level of the atrial Ang Ⅱ and gene expression of atrial integrin β1. （2）Captopril could inhibit the RAS activation and the mRNA expression of atrial integrin β1 leading to atrial structural remodeling in long-term rapid atrial pacing dog models, and might present a new component for the treatment of AF.