Scavenging superoxide selectively in mouse forebrain is associated with improved cardiac function and survival following myocardial infarction.
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.
Lindley
Timothy E
TE
Department of Anatomy, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
Infanger
David W
DW
Rishniw
Mark
M
Zhou
Yi
Y
Doobay
Marc F
MF
Sharma
Ram V
RV
Davisson
Robin L
RL
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
C000606290:SOD1 protein, human; D013481:Superoxides; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1