Abstract 12398: Adenylyl Cyclase 6 Improves Calcium Handling and LV Function in Aging Hearts
Background: Aging heart is characterized by impaired beta-adrenergic receptor signaling and reduced left ventricular (LV) function. We tested the hypothesis that activation of adenylyl cyclase 6 (AC6) expression in cardiac myocytes improves Ca2+ handling and LV function in aging mice.
Methods & Results: Twenty-month-old mice with cardiac-directed and regulated AC6 expression were randomized into two groups, and AC6 expression was activated in one group (AC6-On) but not the other (AC6-Off). One month later, LV function and changes in cardiac myocyte Ca2+ handling were assessed. AC6 expression was associated with increased LV ejection fraction (AC6-Off: 59±3%; AC6-On: 70±4%; P=0.02), and increased systolic elastance (AC6-Off: 1.8±0.6 mmHg/uL; AC6-On: 4.6±1.0 mmHg/uL; P=0.04) (Figure shows representative mice). No changes in LV weight/tibial length ratio, LV fibrosis, expression of fetal genes (atrial natriuretic factor, alpha-skeletal muscle actin, and beta-myosin heavy chain), or expression of collagens were observed in AC6-On mice compared to AC6-Off mice. However, LV samples from AC-On mice showed increased phosphorylation of phospholamban (at Ser16 site; P=0.04) and cardiac troponin I (at Ser23/24 sites; P=0.01), suggesting that AC6 improves Ca2+ handling in aging hearts. Finally, we found that AC6 expression increased caffeine-stimulated Ca2+ transient formation in cardiac myocytes isolated from 23-month-old rats.
Conclusions: These results indicate that activation of cardiac AC6 expression improves function of aging heart, through improved Ca2+ handling.
- © 2010 by American Heart Association, Inc.