title: Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway.
abstract: BACKGROUND
  For reasons that remain unclear, whether type 5 adenylyl cyclase (AC5), 1 of 2 major AC isoforms in heart, is protective or deleterious in response to cardiac stress is controversial. To reconcile this controversy we examined the cardiomyopathy induced by chronic isoproterenol in AC5 transgenic (Tg) mice and the signaling mechanisms involved.
  
  
  RESULTS
  Chronic isoproterenol increased oxidative stress and induced more severe cardiomyopathy in AC5 Tg, as left ventricular ejection fraction fell 1.9-fold more than wild type, along with greater left ventricular dilation and increased fibrosis, apoptosis, and hypertrophy. Oxidative stress induced by chronic isoproterenol, detected by 8-OhDG was 15% greater, P=0.007, in AC5 Tg hearts, whereas protein expression of manganese superoxide dismutase (MnSOD) was reduced by 38%, indicating that the susceptibility of AC5 Tg to cardiomyopathy may be attributable to decreased MnSOD expression. Consistent with this, susceptibility of the AC5 Tg to cardiomyopathy was suppressed by overexpression of MnSOD, whereas protection afforded by the AC5 knockout (KO) was lost in AC5 KO×MnSOD heterozyous KO mice. Elevation of MnSOD was eliminated by both sirtuin and MEK inhibitors, suggesting both the SIRT1/FoxO3a and MEK/ERK pathway are involved in MnSOD regulation by AC5.
  
  
  CONCLUSIONS
  Overexpression of AC5 exacerbates the cardiomyopathy induced by chronic catecholamine stress by altering regulation of SIRT1/FoxO3a, MEK/ERK, and MnSOD, resulting in oxidative stress intolerance, thereby shedding light on new approaches for treatment of heart failure.
authors.affiliation: Department of Cell Biology & Molecular Medicine, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA. vatnerdo@umdnj.edu
authors.forename: Lo
authors.initials: L
authors.lastname: Lai
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.forename: Che-Lin
authors.initials: CL
authors.lastname: Hu
authors.forename: Hui
authors.initials: H
authors.lastname: Ge
authors.forename: Amy
authors.initials: A
authors.lastname: Davidow
authors.forename: Misun
authors.initials: M
authors.lastname: Park
authors.forename: Claudio
authors.initials: C
authors.lastname: Bravo
authors.forename: Kousaku
authors.initials: K
authors.lastname: Iwatsubo
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000503:physiopathology*; D003433:Crosses, Genetic; D003497:Cyclic N-Oxides / Q000627:therapeutic use; D004790:Enzyme Induction / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D007545:Isoproterenol / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D000099156:Superoxide Dismutase 2
chemical_list: D000262:Adenylyl Cyclases; D003497:Cyclic N-Oxides; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007545:Isoproterenol; D047428:Protein Kinase Inhibitors; D056564:Sirtuin 1; D013113:Spin Labels; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C474033:FoxO3 protein, mouse; C470545:Sirt1 protein, mouse; C419510:adenylyl cyclase type V; C001803:tempol
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