Right ventricular beneficial effects of beta adrenergic receptor kinase inhibitor (betaARKct) gene transfer in a rat model of severe pressure overload.
Heart failure is associated with abnormalities in betaAR cascade regulation, calcium cycling, expression of inflammatory mediators and apoptosis. Adenoviral mediated gene transfer of betaARKct has beneficial indirect effects on these pathologic processes upon the left ventricular myocardium. The concomitant biochemical changes that occur in the right ventricle have not been well characterized. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in fractional shortening of 25% from baseline, intracoronary injection of adenoviral-betaARKct (n=14) or adenoviral-beta-galactosidase (control, n=13) was performed. Rats were randomly euthanized on post-operative day 7, 14 or 21. Protein analysis including RV myocardial levels of betaARKct, betaARK1, SERCA(2a), inflammatory tissue mediators (IL-1, IL-6 and TNF-alpha), apoptotic markers (bax and bak), and MAP kinases (jnk, p38 and erk) was performed. ANOVA was employed for group comparison. Adenoviral-betaARKct treated animals showed increased expression of betaARKct and decreased levels of betaARK1 compared with controls. This treatment group also demonstrated normalization of SERCA(2a) expression and decreased levels of the inflammatory markers IL-1, IL-6 and TNF-alpha. The pro-apoptotic markers bax and bak were similarly improved. Ventricular levels of the MAP kinase jnk were increased. 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 the pathologic mechanisms of beta adrenergic receptor desensitization, SERCA(2a) expression, inflammation and apoptosis, not only occur in the left ventricle but also in the right ventricular myocardium after intracoronary gene transfer of betaARKct during heart failure.
Molina
Ezequiel J
EJ
Department of Surgery, Temple University School of Medicine, Philadelphia, PA, USA.
Gupta
Dipin
D
Palma
Jon
J
Gaughan
John P
JP
Macha
Mahender
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006333:Heart Failure / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006352:Heart Ventricles / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010455:Peptides / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis* / Q000235:genetics; D012720:Severity of Illness Index; D019076:Transgenes; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D010455:Peptides; D011994:Recombinant Proteins; C445259:beta-adrenergic receptor kinase inhibitory peptide; D001616:beta-Galactosidase