Scavenging superoxide selectively in mouse forebrain is associated with improved cardiac function and survival following myocardial infarction

Am J Physiol Regul Integr Comp Physiol. 2009 Jan;296(1):R1-8. doi: 10.1152/ajpregu.00078.2008. Epub 2008 Oct 29.


Dysregulation in central nervous system (CNS) signaling that results in chronic sympathetic hyperactivity is now recognized to play a critical role in the pathogenesis of heart failure (HF) following myocardial infarction (MI). We recently demonstrated that adenovirus-mediated gene transfer of cytoplasmic superoxide dismutase (Ad-Cu/ZnSOD) to forebrain circumventricular organs, unique sensory structures that lack a blood-brain barrier and link peripheral blood-borne signals to central nervous system cardiovascular circuits, inhibits both the MI-induced activation of these central signaling pathways and the accompanying sympathoexcitation. Here, we tested the hypothesis that this forebrain-targeted reduction in oxidative stress translates into amelioration of the post-MI decline in myocardial function and increase in mortality. Adult C57BL/6 mice underwent left coronary artery ligation or sham surgery along with forebrain-targeted gene transfer of Ad-Cu/ZnSOD or a control vector. The results demonstrate marked MI-induced increases in superoxide radical formation in one of these forebrain regions, the subfornical organ (SFO). Ad-Cu/ZnSOD targeted to this region abolished the increased superoxide levels and led to significantly improved myocardial function compared with control vector-treated mice. This was accompanied by diminished levels of cardiomyocyte apoptosis in the Ad-Cu/ZnSOD but not the control vector-treated group. These effects of superoxide scavenging with Ad-Cu/ZnSOD in the forebrain paralleled increased post-MI survival rates compared with controls. This suggests that oxidative stress in the SFO plays a critical role in the deterioration of cardiac function following MI and underscores the promise of CNS-targeted antioxidant therapy for the treatment of MI-induced HF.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Apoptosis
  • Disease Models, Animal
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Heart Failure / enzymology
  • Heart Failure / genetics
  • Heart Failure / physiopathology
  • Heart Failure / prevention & control*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Contraction
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / genetics
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / therapy*
  • Myocytes, Cardiac / pathology
  • Oxidative Stress*
  • Prosencephalon / enzymology*
  • Stroke Volume
  • Subfornical Organ / enzymology*
  • Superoxide Dismutase / biosynthesis*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1
  • Superoxides / metabolism*
  • Sympathetic Nervous System / physiopathology
  • Time Factors
  • Transduction, Genetic
  • Ventricular Function, Left
  • Ventricular Pressure


  • SOD1 protein, human
  • Superoxides
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1