Abstract 3216: Activation of Cardiac Adenylyl Cyclase 6 (AC6) Expression Reduces Adverse LV Remodeling and Dysfunction During Pressure Overload
Background. Increased LV AC6 reduces mortality and increases LV function after MI and CHF in mice. However, the effects of increased LV AC6 expression in pressure overload are unknown.
Methods. Transgenic mice with cardiac and tet-regulated AC6 expression and sibling control mice underwent transverse aortic constriction (TAC). Ten days prior to TAC (time required for full expression) AC6 expression was activated by removing doxycycline from the H2O supply in one group (AC6-On) but not the other (AC6-Off). LV systolic and diastolic function were assessed 4w after TAC, and LV â-adrenergic receptor (âAR) signaling, Ca2+ signaling proteins, and apoptosis examined.
Results. TAC induced LV hypertrophy (p<0.001 vs Sham), but showed no group difference (LV/TL: AC6-Off, 9.3±0.7; AC6-On, 8.7±0.6 mg/mm; p=0.5; sham: 5.7±0.3 mg/mm). TAC increased EDD (p<0.001 vs Sham) & decreased FS (p<0.001 vs Sham), but AC6-On showed less LV dilation, better LV function, and a trend toward reduced mortality (Table⇓). Isoproterenol (Iso, 1 μg/g, iv) stimulation showed greater change in peak +dP/dt, peak −dP/dt, and reductions in LVEDP and Tau in AC6-On mice (Table⇓), and LV contractility (Emax) was increased (Table⇓). Phospholamban phosphorylation (PLB-P) was 1.9-fold higher in LV from AC6-On mice (p=0.023), although total PLB, SERCA2a and calsequestrin expression were unchanged. Protein levels of βAR signaling elements (Gs, Gi, GRK2, GRK5, β1AR, β2AR, PKA-catalytic subunit) showed no group differences. Expression of bcl-2, Bax, and caspase-9 were similar, and TUNEL staining showed no difference (5.2±0.6 vs 5.5±1.2 per 10,000 cells; p=0.8)
Conclusions. Activation of cardiac AC6 expression during LV pressure overload reduces LV dilation, increases LV function and tends to decrease mortality. Improved LV remodeling and function were independent of extent of LVH, but were associated with increased LV PLB-P and Ca2+ handling. Increased AC6 has beneficial effects in the pressure overloaded LV.