title: Preserved cardiac function despite marked impairment of cAMP generation.
abstract: OBJECTIVE
  So many clinical trials of positive inotropes have failed, that it is now axiomatic that agents that increase cAMP are deleterious to the failing heart. An alternative strategy is to alter myocardial Ca(2+) handling or myofilament response to Ca(2+) using agents that do not affect cAMP. Although left ventricular (LV) function is tightly linked to adenylyl cyclase (AC) activity, the beneficial effects of AC may be independent of cAMP and instead stem from effects on Ca(2+) handling. Here we ask whether an AC mutant molecule that reduces LV cAMP production would have favorable effects on LV function through its effects on Ca(2+) handling alone.
  
  
  RESULTS
  We generated transgenic mice with cardiac-directed expression of an AC6 mutant (AC6mut). Cardiac myocytes showed impaired cAMP production in response to isoproterenol (74% reduction; p<0.001), but LV size and function were normal. Isolated hearts showed preserved LV function in response to isoproterenol stimulation. AC6mut expression was associated with increased sarcoplasmic reticulum Ca(2+) uptake and the EC50 for SERCA2a activation was reduced. Cardiac myocytes isolated from AC6mut mice showed increased amplitude of Ca(2+) transients in response to isoproterenol (p = 0.0001). AC6mut expression also was associated with increased expression of LV S100A1 (p = 0.03) and reduced expression of phospholamban protein (p = 0.01).
  
  
  CONCLUSIONS
  LV AC mutant expression is associated with normal cardiac function despite impaired cAMP generation. The mechanism appears to be through effects on Ca(2+) handling - effects that occur despite diminished cAMP.
authors.affiliation: VA San Diego Healthcare System and Department of Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Gao
authors.forename: Ngai Chin
authors.initials: NC
authors.lastname: Lai
authors.forename: Tong
authors.initials: T
authors.lastname: Tang
authors.forename: Tracy
authors.initials: T
authors.lastname: Guo
authors.forename: Ruoying
authors.initials: R
authors.lastname: Tang
authors.forename: Byeong Jo
authors.initials: BJ
authors.lastname: Chun
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Dalton
authors.forename: Jorge
authors.initials: J
authors.lastname: Suarez
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Dillmann
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics / Q000378:metabolism; D004452:Echocardiography; D015870:Gene Expression; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D042541:Intracellular Space; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000262:Adenylyl Cyclases; D002118:Calcium; D002135:Calcium-Binding Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D007545:Isoproterenol; D019837:Ryanodine Receptor Calcium Release Channel; D014157:Transcription Factors; D019210:Troponin I; D000099211:Phospholamban; C121100:adenylyl cyclase 6