Adenylyl cyclase 6 improves calcium uptake and left ventricular function in aged hearts

Tong Tang, H. Kirk Hammond, Amy Firth, Yuan Yang, Mei Hua Gao, Jason X.J. Yuan, N. Chin Lai

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1846-1855
Number of pages10
JournalJournal of the American College of Cardiology
Volume57
Issue number18
DOIs
StatePublished - May 3 2011
Externally publishedYes

Keywords

  • adenylyl cyclase
  • calcium uptake
  • cardiac aging
  • extracellular matrix remodeling
  • left ventricular function
  • transgenic mouse

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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