Abstract 1550: Mechanisms for Different Effects of Adenylyl Cyclase Type VI and β1-Adrenergic Receptor Expression on Cardiac Myocytes
Background. Cardiac-directed expression of adenylyl cyclase type VI (ACVI) has pronounced favorable effects on normal and failing hearts, including increased global LV function and increased survival and prevention of adverse remodeling in CHF. In contrast, cardiac expression of β1-adrenergic receptor (β1AR) is associated with apoptosis and induction of CHF. Clearly there are marked differences in effects that are evoked by these two elements of the βAR signaling pathway, even though both increase cAMP. Here we examine the effects of ACVI and β1AR gene transfer in cardiac myocytes on key intracellular signaling pathways.
Methods & Results. Ad.ACVI gene transfer was associated with a 5-fold increase in Akt activity, a protein kinase associated with reduced apoptosis and increased cell survival. We found that increased Akt activity is due to increased phosphorylation of Akt (Figure⇓) through activation of PI3K signaling. In addition, ACVI gene transfer increased both phosphorylation of p70S6 kinase (2-fold) and Bcl-2 (4-fold), events associated with increased Akt activity. In contrast, β1AR gene transfer did not activate PI3K/Akt signaling and did not alter Bcl-2 expression. Indeed, β1AR gene transfer suppressed phosphorylation of p70S6 kinase. All the experiments were repeated at least three times.
Conclusion. PI3K/Akt activation, increased p70S6K signaling and increased Bcl-2 expression are mechanisms underlying the beneficial effects of ACVI. None of these favorable changes are elicited by β1AR expression. These important differences in signaling provide a likely mechanism by which, in contrast to β1AR gene transfer, ACVI gene transfer has salutary effects.