The effects of cilazapril and valsartan on the mRNA and protein expressions of atrial calpains and atrial structural remodeling in atrial fibrillation dogs

被引:60
作者
Li, Yue
Li, Wei-min
Gong, Yong-tai
Li, Bao-xin
Liu, Wei
Han, Wei
Dong, Deli
Sheng, Li
Xue, Jing-yi
Zhang, Li
Chu, Shan
Yang, Bao-feng [1 ]
机构
[1] Harbin Med Univ, Dept Pharmaceut, Harbin 150086, Peoples R China
[2] Harbin Med Univ, Cardiovasc Dept, Clin Hosp 1, Harbin 150001, Peoples R China
[3] Harbin Med Univ, Biopharmaceut Key Lab Heilongjiang Prov & State, Harbin 150086, Peoples R China
关键词
calpains; angiotensin; structural remodelling; atrial fibrillation; dog;
D O I
10.1007/s00395-007-0641-8
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:245 / 256
页数:12
相关论文
共 35 条
[1]   Myocardial cell death in fibrillating and dilated human right atria [J].
Aimé-Sempé, C ;
Folliguet, T ;
Rücker-Martin, C ;
Krajewska, M ;
Krajewski, S ;
Heimburger, M ;
Aubier, M ;
Mercadier, JJ ;
Reed, JC ;
Hatem, SN .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1999, 34 (05) :1577-1586
[2]   Determination of histopathologic risk factors for postoperative atrial fibrillation in cardiac surgery [J].
Ak, K ;
Akgun, S ;
Tecimer, T ;
Isbir, CS ;
Civelek, A ;
Tekeli, A ;
Arsan, S ;
Cobanoglu, A .
ANNALS OF THORACIC SURGERY, 2005, 79 (06) :1970-1975
[3]   Electrical, contractile and structural remodeling during atrial fibrillation [J].
Allessie, M ;
Ausma, J ;
Schotten, U .
CARDIOVASCULAR RESEARCH, 2002, 54 (02) :230-246
[4]  
Ausma J, 2001, CIRCULATION, V104, P77
[5]   Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat [J].
Ausma, J ;
Wijffels, M ;
Thone, F ;
Wouters, L ;
Allessie, M ;
Borgers, M .
CIRCULATION, 1997, 96 (09) :3157-3163
[6]   Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial fibrillation [J].
Brundel, BJJM ;
Kampinga, HH ;
Henning, RH .
CARDIOVASCULAR RESEARCH, 2004, 62 (03) :521-528
[7]   Molecular mechanisms of remodeling in human atrial fibrillation [J].
Brundel, BJJM ;
Henning, RH ;
Kampinga, HH ;
Van Gelder, IC ;
Crijns, HJGM .
CARDIOVASCULAR RESEARCH, 2002, 54 (02) :315-324
[8]  
CONTARD F, 1991, LAB INVEST, V64, P65
[9]  
Dai Youping, 2004, J Huazhong Univ Sci Technolog Med Sci, V24, P32
[10]   Electrical, morphological, and ultrastructural remodeling and reverse remodeling in a canine model of chronic atrial fibrillation [J].
Everett, TH ;
Li, H ;
Mangrum, JM ;
McRury, ID ;
Mitchell, MA ;
Redick, JA ;
Haines, DE .
CIRCULATION, 2000, 102 (12) :1454-1460