Improved Exercise Capacity and Reduced Systemic Inflammation After Adenoviral-Mediated SERCA-2a Gene Transfer

BackgroundWe 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.Materials and methodsA pressure-overload model of experimental heart failure was used in rats. Following a decrease in fractional shortening of ≥25%, animals underwent intracoronary adenoviral-mediated gene transfection using SERCA-2a. Heart failure animals were randomized to receive the SERCA-2a gene, the β 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.ResultsAnimals 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-α 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).ConclusionsGenetic 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.