title: Superoxide scavenging and Akt inhibition in myocardium ameliorate pressure overload-induced NF-κB activation and cardiac hypertrophy.
abstract: Recent studies from our laboratory and others have shown that increases in cytoplasmic superoxide (O(2)(·-)) levels and Akt activation play a key role in agonist-stimulated NF-κB activation and cardiomyocyte hypertrophy in vitro. In this study, we tested the hypothesis that adenovirus (Ad)-mediated intramyocardial gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD) or a dominant-negative form of Akt (AdDNAkt) in mice would attenuate pressure overload-induced increases in activation of the redox-sensitive transcription factor NF-κB and cardiac hypertrophy. Adult C57BL/6 mice were subjected to thoracic aortic banding (TAB) or sham surgery, and intramyocardial injections of viral vectors (AdCu/ZnSOD, AdDNAkt, or control) were performed. There was robust transgene expression in the heart, which peaked 6-7 days after injection and then declined to undetectable levels by 12-14 days. In mice injected with AdBgL II, TAB caused a significant increase in O(2)(·-) generation and cardiac mass at 1 wk, and these responses were markedly attenuated by AdCu/ZnSOD. In addition, TAB induced time-dependent activation of NF-κB in the myocardium as measured longitudinally by in vivo bioluminescent imaging of NF-κB-dependent luciferase expression. This was also abolished by intracardiac AdCu/ZnSOD or AdDNAkt, but not the control vector. The inhibition of Akt and O(2)(·-)-mediated NF-κB activation in TAB hearts was associated with an attenuation of cardiac hypertrophy. Since a direct cause-and-effect relationship between NF-κB activation and cardiomyocyte hypertrophy has been established previously, our data support the hypothesis that increased O(2)(·-) generation and Akt activation are key signaling intermediates in pressure overload-induced activation of NF-κB and cardiac hypertrophy.
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Hingtgen
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Li
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
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; D004195:Disease Models, Animal; D004789:Enzyme Activation; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D016328:NF-kappa B; D013481:Superoxides; D013482:Superoxide Dismutase; D051057:Proto-Oncogene Proteins c-akt