title: Activated expression of cardiac adenylyl cyclase 6 reduces dilation and dysfunction of the pressure-overloaded heart.
abstract: OBJECTIVE
  Cardiac-directed adenylyl cyclase 6 (AC6) expression attenuates left ventricular (LV) hypertrophy and dysfunction in cardiomyopathy, but its effects in the pressure-overloaded heart are unknown.
  
  
  METHODS
  Mice with cardiac-directed and regulated expression of AC6 underwent transaortic constriction (TAC) to induce LV pressure overload. Ten days prior to TAC, and for the duration of the 4 week study, cardiac myocyte AC6 expression was activated in one group (AC-On) but not the other (AC-Off). Multiple measures of LV systolic and diastolic function were obtained 4 weeks after TAC, and LV samples assessed for alterations in Ca2+ signaling.
  
  
  RESULTS
  LV contractility, as reflected in the end-systolic pressure-volume relationship (Emax), was increased (p=0.01) by activation of AC6 expression. In addition, diastolic function was improved (p<0.05) and LV dilation was reduced (p<0.05). LV samples from AC-On mice showed reduced protein expression of sodium/calcium exchanger (NCX1) (p<0.05), protein phosphatase 1 (PP1) (p<0.01), and increased phosphorylation of phospholamban (PLN) at Ser16 (p<0.05). Finally, sarcoplasmic reticulum (SR) Ca2+ content was increased in cardiac myocytes isolated from AC-On mice (p<0.05).
  
  
  CONCLUSIONS
  Activation of cardiac AC6 expression improves function of the pressure-overloaded and failing heart. The predominant mechanism for this favorable adaptation is improved Ca2+ handling, a consequence of increased PLN phosphorylation, reduced NCX1, reduced PP1 expression, and increased SR Ca2+ content.
authors.affiliation: Department of Medicine, UC San Diego, VA San Diego Healthcare System, San Diego, CA 92161, USA.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sugano
authors.forename: N Chin
authors.initials: NC
authors.lastname: Lai
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Gao
authors.forename: Amy L
authors.initials: AL
authors.lastname: Firth
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.forename: Wilbur Y W
authors.initials: WY
authors.lastname: Lew
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
mesh_terms: D000262:Adenylyl Cyclases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004108:Dilatation, Pathologic / Q000201:enzymology / Q000503:physiopathology; D004789:Enzyme Activation; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011312:Pressure; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000503:physiopathology*; D000099211:Phospholamban
chemical_list: D000262:Adenylyl Cyclases; D002110:Caffeine; D002118:Calcium; D002135:Calcium-Binding Proteins; D017476:Receptors, Neuropeptide Y; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C499849:NCX1 protein, mouse; C109491:neuropeptide Y4 receptor; C121100:adenylyl cyclase 6