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Am J Physiol Regul Integr Comp Physiol (October 29, 2008). doi:10.1152/ajpregu.00078.2008
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Submitted on February 1, 2008
Accepted on October 27, 2008

Scavenging Superoxide Selectively in Mouse Forebrain is Associated with Improved Cardiac Function and Survival Following Myocardial Infarction

Timothy Eric Lindley1, David W. Infanger2, Mark Rishniw3, Yi Zhou4, Marc F Doobay1, Ram V. Sharma5, and Robin L. Davisson6*

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

* To whom correspondence should be addressed. E-mail: rld44{at}cornell.edu.

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 CNS 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 the 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 to 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 to 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.




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