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Physiological and Molecular Mechanisms Implicated in the Neural Control of Circulation

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

¹Department of Anatomy and Cell Biology, ²Free Radical and Radiation Biology Program, Department of Radiation Oncology, ³The Cardiovascular Center, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa; ⁴Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York; and ⁵Department of Cell and Developmental Biology, Weill Cornell Medical College, Cornell University, New York, New York

Submitted 1 February 2008 ; accepted in final form 27 October 2008

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.

heart failure; antioxidant gene therapy; survival; sympathetic nervous system

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