The effects of cilazapril and valsartan on the mRNA and protein expressions of atrial calpains and atrial structural remodeling in atrial fibrillation dogs
The effects of cilazapril and valsartan on the mRNA and protein expressions of atrial calpains and atrial structural remodeling in atrial fibrillation dogs
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DOI：
10.1007/s00395-007-0641-8
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发表时间：
2007-05-01
影响因子：
9.5
通讯作者：
Yang, Bao-feng
中科院分区：
文献类型：
--
作者：
Li, Yue;Li, Wei-min;Yang, Bao-feng
由于目前可用的抗心律失常药物相对无效和副作用，目前的兴趣已转移到针对心房颤动（AF）底物的治疗。心房颤动时钙蛋白酶诱导的心房结构重构受肾素-血管紧张素系统控制。本研究旨在探讨西拉普利和缬沙坦对慢性快速心房起搏诱发的心房颤动犬心房钙蛋白酶mRNA和蛋白表达及心房结构重构的影响。27只狗随机分为假手术组（n = 6）、对照组（n = 7）、西拉普利组（n = 7）和缬沙坦组（n = 7）。在每个心房上缝合一个包含4对电极的薄硅斑块。起搏器被植入皮下口袋，并连接到右心房附件的螺旋心外膜导线上。对照组、西拉普利组和缬沙坦组均以400次/分的心率给药，连续6周。西拉普利组和缬沙坦组在快速心房起搏前1周分别给予西拉普利（1mg中心点kg（-1）中心点d(-1)）或缬沙坦（30mg中心点kg（-1）中心点d(-1)），直至起搏停止。经胸、经食管超声心动图检查左心房容积和收缩功能的变化。测定各组AF的诱导率和持续时间。逆转录聚合酶链反应半定量心房钙蛋白酶I和钙蛋白酶II mRNA的表达。Western-blot法检测大鼠心房心肌钙蛋白酶ⅰ（calpain I）和钙蛋白酶ⅱ（calpain II）蛋白水平。光镜、电镜观察心房组织病理组织学和超微结构变化。与假手术对照组相比，西拉普利组和缬沙坦组左心房和左心房附件体积明显缩小，心房收缩功能明显提高。心房心动过速6周后，对照组calpain I mRNA和蛋白表达量均显著高于假手术组，各组组织calpain蛋白表达量与肌溶解呈显著相关（r = 0.89, P < 0.01）。西拉普利和缬沙坦均能显著抑制calpain i基因和蛋白的表达，各组间calpain II mRNA和蛋白的表达均无差异。与假犬心房肌细胞相比，对照组心房肌细胞肌瘤数量减少，心房肌溶解面积显著增加（24.3%比3.1%,P < 0.01），空泡化和溶解增加。西拉普利和缬沙坦能有效预防慢性快速心房起搏引起的病理组织学和超微结构改变，显著减少心房颤动的肌溶面积（P < 0.05），显著降低心房颤动的诱导性和持续时间。心房颤动犬calpain I mRNA和蛋白表达显著升高。西拉普利和缬沙坦可抑制慢性快速心房起搏犬calpain I上调，抑制心房结构重构，防止诱发和促进房颤。
Owing to relative inefficacy and side effects of currently available antiarrhythmic drugs, current interest has shifted to treatments that target atrial fibrillation (AF) substrate. It has been suggested that calpain-induced atrial structural remodelling is under the control of renin-angiotensin system during AF. The purpose of this study is to investigate the effects of cilazapril and valsartan on the mRNA and protein expression of atrial calpains and atrial structural remodelling in AF dogs induced by chronic rapid atrial pacing. Twenty-seven dogs were randomly divided into sham-operated group (n = 6), control group (n = 7), cilazapril group (n = 7) and valsartan group (n = 7). One thin silicon plaque containing 4 pairs of electrodes was sutured to each atrium. A pacemaker was implanted in a subcutaneous pocket and attached to a screw-in epicardial lead in the right atrial appendage. The dogs in control group, cilazapril group and valsartan group were paced at 400 beats per minutes for 6 weeks. The dogs in cilazapril and valsartan groups received cilazapril (1mg center dot kg(-1)center dot d(-1)) or valsartan (30mg center dot kg(-1)center dot d(-1)) 1 week before rapid atrial pacing until pacing stop respectively. Transthoracic and transoesophageal echocardiographic examinations were performed in order to detect the changes of left atrium volume and contractile function. The inducibility and duration of AF were measured in all the groups. The expressions of atrial calpain I and calpain II mRNA were semi-quantified by reverse transcription-polymerase chain reaction. The protein levels of calpain I and calpain II in atrial myocardium were measured by Western-blot method. Pathohistological and ultrastructural changes in atrial tissue were tested by light and electron microscopy. Compared with the sham-operated control group, dramatic smaller left atrium and left atrial appendage volumes and significant higher atrial contractile function were observed in the cilazapril and valsartan groups. After 6-week atrial tachy-pacing, the mRNA and protein expressions of calpain I increased dramatically in the control group than that in the sham group, tissue calpain protein expression in all groups significantly correlated with the myolysis (r = 0.89, P < 0.01). Cilazapril and valsartan could significantly inhibit the gene and protein expressions of calpain I. No differences were found in the expression of calpain II mRNA and protein between the groups. Compared with atrial myocytes obtained from sham dogs, atrial myocytes from the control group dogs showed a reduced number of sarcomeres, a significant higher myolytic area of atria (24.3% vs. 3.1%, P < 0.01), increased vacuolization and dissolution. Cilazapril and valsartan could effectively prevent the pathohistological and ultrastructural changes induced by chronic rapid atrial pacing, dramatically decrease the area of myolysis (P < 0.05) and significantly reduce the inducibility and duration of AF. The expression of calpain I mRNA and protein increased remarkably in AF dogs. Cilazapril and valsartan can inhibit calpain I up-regulation, suppress atrial structural remodeling, and prevent the induction and promotion of AF in chronic rapid atrial pacing dogs.