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

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.

journal_name

J Am Coll Cardiol

journal_title

Journal of the American College of Cardiology

authors

Tang T,Hammond HK,Firth A,Yang Y,Gao MH,Yuan JX,Lai NC

doi

10.1016/j.jacc.2010.11.052

subject

Has Abstract

pub_date

2011-05-03 00:00:00

pages

1846-55

issue

eissn

0735-1097

issn

1558-3597

pii

S0735-1097(11)00620-6

journal_volume

pub_type

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