title: Increased cardiac adenylyl cyclase expression is associated with increased survival after myocardial infarction.
abstract: BACKGROUND
  Cardiac-directed expression of adenylyl cyclase type VI (AC(VI)) in mice results in structurally normal hearts with normal basal heart rate and function but increased responses to catecholamine stimulation. We tested the hypothesis that increased left ventricular (LV) AC(VI) content would increase mortality after acute myocardial infarction (MI).
  
  
  RESULTS
  Transgenic mice with cardiac-directed AC(VI) expression and their transgene-negative littermates (control) underwent coronary ligation, and survival, infarct size, and LV size and function were assessed 1 to 7 days after MI. Mice with increased AC(VI) expression had increased survival (control 41%, AC(VI) 74%; P = 0.004). Infarct size and myocardial apoptotic rates were similar in AC(VI) and control mice; however, AC(VI) mice had less LV dilation (P < 0.001) and increased ejection fractions (P < 0.03). Three days after MI, studies in isolated perfused hearts showed that basal LV +dP/dt was similar, but graded dobutamine infusion was associated with a more robust LV contractile response in AC(VI) mice (P < 0.05). Increased LV function was associated with increases in cAMP generation (P = 0.0002), phospholamban phosphorylation (P < 0.04), sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) affinity for calcium (P < 0.015), and reduced AV block (P = 0.04).
  
  
  CONCLUSIONS
  In acute MI, increased cardiac AC(VI) content attenuates adverse LV remodeling, preserves LV contractile function, and reduces mortality.
authors.affiliation: Department of Medicine, University of California, San Diego, Calif., USA.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tong
authors.initials: T
authors.lastname: Tang
authors.forename: N Chin
authors.initials: NC
authors.lastname: Lai
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: Brian
authors.initials: B
authors.lastname: Rebolledo
authors.forename: Miho
authors.initials: M
authors.lastname: Saito
authors.forename: Wilbur Y W
authors.initials: WY
authors.lastname: Lew
authors.forename: Paul
authors.initials: P
authors.lastname: Clopton
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
mesh_terms: D000262:Adenylyl Cyclases / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000032:analysis / Q000502:physiology; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006352:Heart Ventricles / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology*; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015996:Survival Rate; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D002118:Calcium