Abstract 19097: Enhanced Beta-Adrenergic Signaling Reverses Atrophic Gene Regulation in the Unloaded Heart
Objective: Mechanical unloading via a left ventricular assist device (LVAD) results in beneficial reversal of hypertrophy and reinstated adrenergic response as well as detrimental progressive atrophy and currently efforts are made towards limitation of this atrophy to promote ventricular recovery using beta-adrenergic agonist. We have previously shown that the βARKct peptide inhibits desensitizing of β-adrenergic receptor signaling to enhance regenerative capacity in failing hearts via virus-mediated gene therapy. Treatment of unloaded hearts with βARKct adeno-associated virus-6 (AAV6) was assessed using a gene array to identify potential beneficial and anti-atrophic effects.
Methods: Non-failing rat hearts were heterotopically transplanted, treated with different doses of AAV6-βARKct (1011 and 6x1011 total viral particles) and harvested after 3 and 30 days of unloading (n=6/group). Total mRNA was purified and an array of 47 genes was analyzed using microfluid cards.
Results: Several genes involved in myocyte calcium cycling (Ryanodine Receptor-2, SERCA2a, Phospholamban), cardiac metabolism (Glycogen-Synthase, Glycerol-3-phosphate-dehydrogenase) and cellular integrity (Troponin-C, -T and -I) were significantly downregulated in unloaded hearts, but significantly recovered towards control levels in the βARKct-treated groups showing a dose dependent effect. Matrix remodeling reflected by Fibroblast Growth Factor-2 was upregulated 4-fold (±1.5) at 3 days in controls, but showed normalization after βARKct gene therapy in unloaded hearts. Expression of fetal genes (MHC-β, MHC-α) remained switched. Caspase-9 reflecting induced apoptosis was briefly induced after 3 days, but normalized thereafter independent of treatment.
Conclusion: Recent clinical studies have associated treatment with a beta-adrenergic agonist with enhanced rate of recovery through improved ventricular function. Our results suggest that unloading-induced atrophy may be limited by enhanced β-adrenergic signalling and introduce bARKct gene therapy as a promising tool for LVAD therapy towards myocardial recovery.
- © 2010 by American Heart Association, Inc.