Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway

Circulation. 2013 Apr 23;127(16):1692-701. doi: 10.1161/CIRCULATIONAHA.112.001212. Epub 2013 Mar 27.

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.

Methods and 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / deficiency
  • Adenylyl Cyclases / genetics
  • Adenylyl Cyclases / physiology*
  • Animals
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / physiopathology*
  • Crosses, Genetic
  • Cyclic N-Oxides / therapeutic use
  • Enzyme Induction / physiology
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / physiology*
  • Isoproterenol / toxicity
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology*
  • Protein Kinase Inhibitors / pharmacology
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / physiology*
  • Spin Labels
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / physiology*
  • Transcription, Genetic

Substances

  • Cyclic N-Oxides
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • Protein Kinase Inhibitors
  • Spin Labels
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Adenylyl Cyclases
  • adenylyl cyclase type V
  • Isoproterenol
  • tempol