Right ventricular beneficial effects of beta adrenergic receptor kinase inhibitor (βARKct) gene transfer in a rat model of severe pressure overload

Heart failure is associated with abnormalities in βAR cascade regulation, calcium cycling, expression of inflammatory mediators and apoptosis. Adenoviral mediated gene transfer of βARKct 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-βARKct (n = 14) or adenoviral-β-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 βARKct, βARK1, SERCA2a, inflammatory tissue mediators (IL-1, IL-6 and TNF-α), apoptotic markers (bax and bak), and MAP kinases (jnk, p38 and erk) was performed. ANOVA was employed for group comparison. Adenoviral-βARKct treated animals showed increased expression of βARKct and decreased levels of βARK1 compared with controls. This treatment group also demonstrated normalization of SERCA2a expression and decreased levels of the inflammatory markers IL-1, IL-6 and TNF-α. 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, SERCA2a expression, inflammation and apoptosis, not only occur in the left ventricle but also in the right ventricular myocardium after intracoronary gene transfer of βARKct during heart failure.