[Treatment of chronic heart failure by overexpressing sarcoplasmic reticulum calcium ATPase through gene therapy: an experiment with rats].
OBJECTIVE
To evaluate the value of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in the gene therapy of congestive heart failure.


METHODS
(1) The abdominal aortas of 51 male SD rats were isolated and ligated so as to establish models of heart failure caused by contraction of abdominal aortas. 20 rats undergoing isolation of the abdominal aorta without ligation were used as controls. 18 approximately 20 days after the operation heart failure occurred, then the rats with contraction of abdominal aorta and heart failure were randomly divided into 3 groups: rAAV-SERCA2a group (recombinant adeno-associated virus containing SERCA2a cDNA, rAAV-SERCA2a, of the concentration of 2 x 10(11) v.g was injected via diaphragm into the pericardia cavity), heart failure control group (without trentment) and rAAV2-EGFP group (the control virus rAAV2-EGFP of the concentration of 2 x 10(11) v.g was injected via diaphragm into the pericardial cavity). 10 and 30 days after virus injection, a catheter was inserted through the jugular vein into the left ventricle to record the left ventricle systole pressure (LVSP), left ventricle end diastole pressure (LVEDP), left ventricle pressure maximum increase speed (+dp/dt), and left ventricle pressure maximum decrease speed (-dp/dt), and heart rate (HR). Then all the rats were killed and their hearts were taken out to examine the expression of the SERCA2a protein. (2) The left coronary arteries of 25 male SD rats were ligated so as to establish the models of cardiac infarction. 9 rats underwent isolation of the left coronary arteries without ligation and were used as controls. Four weeks after the operation thoracotomy was performed on the rats with heart failure caused by heart infarction, rAV-SERCA2a or rAV2-EGFP were injected into the myocardium, and dilute solution was injected to the control rats. 21 days later all the rats were performed hemodynamic exams.


RESULTS
(1) Thirty days after the transfection the LVSP, +dp/dt, and -dp/dt of the rAAV-SERCA2a group were significantly higher than those of the rAAV2-EGFP group by 57% (94 mm Hg vs 147 mm Hg), 110% (5350 mm Hg/s vs 11 225 mm Hg/s), and 99.8% (4198 mm Hg/s vs 8390 mm Hg/s) respectively, meanwhile the LVEDP was significantly lower by 60% (22 mm Hg vs 9 mm Hg). These homodynamic parameters of the rAAV-SERCA2a group were not significantly different from those of the control group. Thirty days after transfection the expression of SERCA2a protein of the SERCA2a group was significantly higher than those of the control heart failure and rAAV2-EGFP groups. (2) Twenty-one days after the transfection, the LVSP, +dp/dt, and -dp/dt of the SERCA2a group were significantly higher than those of the control group by 28% (86 mm Hg vs 110 mm Hg), 41% (4272 mm Hg/s vs 6026 mm Hg/s), and 71% (2789 mm Hg/s vs 4756 mm Hg/s) respectively, and the LVEDP was significantly lower by 70% (3.89 mm Hg vs -5.34 mm Hg), however, these homodynamic parameters of the rAV-SERCA2a group were all worse compared with the control false operation group.


CONCLUSIONS
The recombinant viruses, rAAV-SERCA2a and rAV-SERCA2a, effectively deliver the SERCA2a gene and improve the homodynamic state.
Li
Xiao-Ying
XY
Department of Geriatric Cardiology, General Hospital of People's Liberation Army, Beijing 100853, China.
Hui
Hai-Peng
HP
Lu
Xiao-Chun
XC
Guo
Yu-Tao
YT
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D002908:Chronic Disease; D003251:Constriction, Pathologic / Q000150:complications; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000209:etiology / Q000628:therapy*; D008026:Ligation / Q000009:adverse effects; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases