Superoxide is involved in the central nervous system activation and sympathoexcitation of myocardial infarction-induced heart failure.
Increased angiotensin II signaling in the brain has been shown to play a critical role in the excessive sympathoexcitation and development of heart failure (HF) after myocardial infarction (MI). We have recently demonstrated that reactive oxygen species mediate the actions of angiotensin II in the brain. In this study, we tested the hypothesis that increased redox signaling in central cardiovascular control regions is a key mechanism in the neurocardiovascular dysregulation that follows MI. Ligation of the left coronary artery induced a large MI and subsequent HF in adult C57BL/6 mice, as demonstrated by cardiac hypertrophy, hydrothorax, and ascites. Immunohistochemical analysis of Fos, a marker of neuronal activation, revealed a significant increase in the number of Fos-positive neurons in the paraventricular nucleus and supraoptic nucleus at 2 and 4 weeks after MI compared with sham mice. Intracerebroventricular injection of an adenoviral vector encoding superoxide dismutase (Ad-Cu/ZnSOD) caused a significant decrease in the number of Fos-positive neurons in the paraventricular nucleus and supraoptic nucleus at 2 weeks after MI compared with mice receiving either saline or a control vector (Ad-LacZ). There was also a diminished role of sympathetic drive in post-MI mice treated centrally with Ad-Cu/ZnSOD, as demonstrated by significantly attenuated falls in heart rate and mean arterial pressure to the ganglionic blocker hexamethonium and decreased urinary norepinephrine levels in these mice compared with Ad-LacZ-treated MI mice. These results suggest that superoxide plays a key role in the central activation and sympathetic hyperactivity after MI in mice and that oxygen radicals in the brain may be important new targets for therapeutic treatment of heart failure.
Lindley
Timothy E
TE
Department of Anatomy and Cell Biology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA.
Doobay
Marc F
MF
Sharma
Ram V
RV
Davisson
Robin L
RL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006333:Heart Failure / Q000209:etiology* / Q000503:physiopathology; D006801:Humans; D007276:Injections, Intraventricular; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D000959:Antihypertensive Agents; D016760:Proto-Oncogene Proteins c-fos; D013481:Superoxides; D013482:Superoxide Dismutase; D019808:Losartan