title: In vivo bioluminescence imaging reveals redox-regulated activator protein-1 activation in paraventricular nucleus of mice with renovascular hypertension.
abstract: Renovascular hypertension in mice is characterized by an elevation in hypothalamic angiotensin II levels. The paraventricular nucleus (PVN) is a major cardioregulatory site implicated in the neurogenic component of renovascular hypertension. Increased superoxide (O(2)(-·)) production in the PVN is involved in angiotensin II-dependent neurocardiovascular diseases such as hypertension and heart failure. Here, we tested the hypothesis that excessive O(2)(-·) production and activation of the redox-regulated transcription factor activator protein-1 (AP-1) in PVN contributes to the development and maintenance of renovascular hypertension. Male C57BL/6 mice underwent implantation of radiotelemeters, bilateral PVN injections of an adenovirus (Ad) encoding superoxide dismutase (AdCuZnSOD) or a control gene (LacZ), and unilateral renal artery clipping (2-kidney, one-clip [2K1C]) or sham surgery. AP-1 activity was longitudinally monitored in vivo by bioluminescence imaging in 2K1C or sham mice that had undergone PVN-targeted microinjections of an Ad encoding the firefly luciferase (Luc) gene downstream of AP-1 response elements (AdAP-1Luc). 2K1C evoked chronic hypertension and an increase in O(2)(-·) production in the PVN. Viral delivery of CuZnSOD to the PVN not only prevented the elevation in O(2)(-·) but also abolished renovascular hypertension. 2K1C also caused a surge in AP-1 activity in the PVN, which paralleled the rise in O(2)(-·) production in this brain region, and this was prevented by treatment with AdCuZnSOD. Finally, Ad-mediated expression of a dominant-negative inhibitor of AP-1 activity in the PVN prevented 2K1C-evoked hypertension. These results implicate oxidant signaling and AP-1 transcriptional activity in the PVN as key mediators in the pathogenesis of renovascular hypertension.
authors.affiliation: Biomedical Sciences, College of Veterinary Medicine, Weill Cornell Medical College, Cornell University, Ithaca, NY 14853-6401, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Burmeister
authors.forename: Colin N
authors.initials: CN
authors.lastname: Young
authors.forename: Valdir A
authors.initials: VA
authors.lastname: Braga
authors.forename: Scott D
authors.initials: SD
authors.lastname: Butler
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; D001284:Atrophy; D001794:Blood Pressure; D006339:Heart Rate; D006978:Hypertension, Renovascular / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010084:Oxidation-Reduction; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D013481:Superoxides; D008156:Luciferases; D013482:Superoxide Dismutase