Author + information
- Received September 1, 2010
- Revision received November 9, 2010
- Accepted November 9, 2010
- Published online May 3, 2011.
- Tong Tang, PhD⁎,†,⁎ (, )
- H. Kirk Hammond, MD⁎,†,
- Amy Firth, PhD†,
- Yuan Yang, MD†,
- Mei Hua Gao, PhD⁎,†,
- Jason X.-J. Yuan, MD, PhD† and
- N. Chin Lai, PhD⁎,†
- ↵⁎Reprint requests and correspondence:
Dr. Tong Tang, VA San Diego Healthcare System (111A), 3350 La Jolla Village Drive, San Diego, California 92161
Objectives This study tested the hypothesis that activation of adenylyl cyclase 6 (AC6) expression in cardiac myocytes improves calcium uptake and left ventricular (LV) function in aging mice.
Background Aging hearts exhibit impaired β-adrenergic receptor signaling and LV dysfunction.
Methods Twenty-month-old mice with cardiac-directed and regulated AC6 expression were randomized into 2 groups, and AC6 expression was activated in 1 group (AC6-On) but not the other (AC6-Off). One month later, LV function and sarcoplasmic reticulum calcium uptake were assessed.
Results AC6 expression was associated with increased LV contractility, as reflected by ejection fraction (p = 0.02), rate of pressure development (p = 0.002), and slope of the LV end-systolic pressure-volume relationship (p = 0.04). No changes in LV weight to tibial length ratio, LV fibrosis, and expression of fetal genes (atrial natriuretic factor, α-skeletal muscle actin, and β-myosin heavy chain) and collagens were observed between AC6-On and AC6-Off groups. However, LV samples from AC6-On mice showed increases in: isoproterenol-stimulated cAMP production (p = 0.04), cAMP-dependent protein kinase activity (p < 0.0004), phosphorylation of phospholamban (at Ser16 site; p = 0.04) and cardiac troponin I (at Ser23/24 sites; p = 0.01), velocity of sarcoplasmic reticulum calcium uptake (p < 0.0001), and sarcoplasmic reticulum calcium-ATPase2a (SERCA2a) affinity for calcium (p < 0.0001). Finally, we found that AC6 expression increased sarcoplasmic reticulum calcium storage in cardiac myocytes isolated from 23-month-old rats. In contrast, AC6 expression in 7-month-old mice did not change LV function and calcium uptake.
Conclusions These results indicate that activation of cardiac AC6 expression improves impaired function of aged hearts through improved calcium uptake.
- adenylyl cyclase
- calcium uptake
- cardiac aging
- extracellular matrix remodeling
- left ventricular function
- transgenic mouse
This work was supported by Grants-in-Aid from the American Heart Association Western States Affiliate, NIH grants (5P01HL066941, HL081741, HL088426), and a VA Merit Review Award. Dr. Hammond is a founder, consultant, and equity holder for Renova Therapeutics. All other authors have reported that they have no relationships to disclose. Douglas Mann, MD, acted as Guest Editor for this article.
- Received September 2010.
- Revision received November 9, 2010.
- Accepted November 9, 2010.
- American College of Cardiology Foundation