Improved exercise capacity and reduced systemic inflammation after adenoviral-mediated SERCA-2a gene transfer.
BACKGROUND
We hypothesized that sarcoplasmic reticulum Ca2+ ATPase pump (SERCA-2a) gene delivery would have beneficial effects upon exercise capacity and markers of inflammation in the setting of heart failure.


METHODS
A pressure-overload model of experimental heart failure was used in rats. Following a decrease in fractional shortening of >or=25%, animals underwent intracoronary adenoviral-mediated gene transfection using SERCA-2a. Heart failure animals were randomized to receive the SERCA-2a gene, the beta galactosidase (control) gene, or followed without any further intervention. Exercise and hemodynamic testing were performed, and myocardial and systemic markers of inflammation were assayed after 7 and 21 d.


RESULTS
Animals receiving Ad.SERCA-2a showed an increase in exercise tolerance (499.0 +/- 14.9 versus 312.8 +/- 10.5 s, P < 0.0001) relative to Ad.Gal group. Groups treated with Ad.SERCA-2a had significantly decreased serum levels of the inflammatory markers interleukin-1, interleukin-6, and tumor necrosis factor-alpha compared with Ad.Gal-treated animals. Serum levels of atrial natriuretic peptide were decreased in animals receiving Ad.SERCA-2a compared with animals receiving Ad.Gal at day 7 (0.35 +/- 0.03 versus 0.52 +/- 0.11 pg/mL, P = 0.001). Myocardial levels of the proapoptotic protein bax were reduced in Ad.SERCA-2a -treated animals compared with those receiving Ad.Gal at day 7 (protein level/actin: 0.24 +/- 0.05 versus 0.33 +/- 0.04, P = 0.04) and day 21 (protein level/actin: 0.61 +/- 0.04 versus 0.69 +/- 0.01, P = 0.001).


CONCLUSIONS
Genetic modulation of heart failure using the SERCA-2a gene was associated with improvement in cardiac function and exercise capacity as well as improvements in heart-failure associated inflammatory markers.
Gupta
Dipin
D
Department of Cardiac and Thoracic Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Palma
Jon
J
Molina
Ezequiel
E
Gaughan
John P
JP
Long
Walter
W
Houser
Steven
S
Macha
Mahender
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D009202:Cardiomyopathies / Q000276:immunology / Q000503:physiopathology / Q000628:therapy; D003971:Diastole; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D006339:Heart Rate; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D009206:Myocardium / Q000473:pathology; D010805:Physical Conditioning, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D013599:Systole; D014883:Water-Electrolyte Imbalance
D015415:Biomarkers; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases