title: Adenylyl cyclase 6 improves calcium uptake and left ventricular function in aged hearts.
abstract: OBJECTIVE
  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.
authors.affiliation: VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. ttang@vapop.ucsd.edu
authors.forename: Tong
authors.initials: T
authors.lastname: Tang
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
authors.forename: Amy
authors.initials: A
authors.lastname: Firth
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Gao
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.forename: N Chin
authors.initials: NC
authors.lastname: Lai
mesh_terms: D000262:Adenylyl Cyclases / Q000502:physiology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004452:Echocardiography; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013318:Stroke Volume / Q000502:physiology; D013752:Tetracycline / Q000494:pharmacology; D019210:Troponin I / Q000032:analysis; D016277:Ventricular Function, Left / Q000502:physiology*; D000099211:Phospholamban
chemical_list: D000262:Adenylyl Cyclases; D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D011500:Protein Synthesis Inhibitors; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013752:Tetracycline; D019210:Troponin I; D000099211:Phospholamban; C121100:adenylyl cyclase 6