title: Scavenging superoxide selectively in mouse forebrain is associated with improved cardiac function and survival following myocardial infarction.
abstract: 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.
authors.affiliation: Department of Anatomy, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Lindley
authors.forename: David W
authors.initials: DW
authors.lastname: Infanger
authors.forename: Mark
authors.initials: M
authors.lastname: Rishniw
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Marc F
authors.initials: MF
authors.lastname: Doobay
authors.forename: Ram V
authors.initials: RV
authors.lastname: Sharma
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D018384:Oxidative Stress; D016548:Prosencephalon / Q000201:enzymology*; D013318:Stroke Volume; D013356:Subfornical Organ / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000503:physiopathology; D013997:Time Factors; D014161:Transduction, Genetic; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: C000606290:SOD1 protein, human; D013481:Superoxides; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1