Right ventricular beneficial effects of intracoronary SERCA2a gene transfer in an experimental model of heart failure.
SERCA2a gene transfer ameliorates heart failure pathologic processes in left ventricular myocardium. We sought to assess the simultaneous molecular changes that occur in the right ventricle. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography for development of heart failure. After a decrease in fractional shortening of 25 % from baseline, intracoronary injection of adenoviral-SERCA2a or adenoviral-beta-galactosidase was performed. Successful gene transfer was confirmed by immunoblotting. Rats were randomly euthanized on post-operative day 7 or 21. Protein analysis including right ventricular levels of SERCA2a, betaARK1, inflammatory mediators (IL-1, IL-6 and TNF-alpha), apoptotic markers (Bax, Bak and Bcl-2) and MAPK (Jnk, p38 and Erk) was performed. Adenoviral-SERCA2a-treated animals showed increased right ventricular expression of SERCA2a compared with controls. Decreased levels of inflammatory markers were also demonstrated in this group. Expression of pro-apoptotic markers was similarly improved. Levels of MAPK were increased compared with the control group. These differences were most significant 7 days after gene transfer, but the majority of these changes persisted at 21 days. These results suggest that attenuation of pathologic mechanisms of calcium cycling, inflammation and apoptosis also occur in the right ventricular myocardium after SERCA2a gene transfer during heart failure. These findings support a therapeutic role for genetic manipulation of this pathway in patients with right ventricular or biventricular failure.
Molina
E J
EJ
Department of Surgery, Temple University School of Medicine, Philadelphia, PA, USA.
Gupta
D
D
Palma
J
J
Gaughan
J P
JP
Macha
M
M
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D014779:Virus Replication
D015415:Biomarkers; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases