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

• Published in: Basic research in cardiology 2007-05, Vol.102 (3), p.245-256
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Atrial Fibrillation - genetics; Atrial Fibrillation - physiopathology; Blotting, Western; Calpain - biosynthesis; Cilazapril - pharmacology; Disease Models, Animal; Dogs; Female; Gene Expression - drug effects; Gene Expression Regulation - drug effects; Heart Atria - diagnostic imaging; Heart Atria - physiopathology; Male; Myocytes, Cardiac - pathology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; Tetrazoles - pharmacology; Ultrasonography; Valine - analogs & derivatives; Valine - pharmacology; Valsartan
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-007-0641-8

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 x kg(-1)x d(-1)) or valsartan (30mg x kg(-1) x 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 d