Increased mitochondrial superoxide in the brain, but not periphery, sensitizes mice to angiotensin II-mediated hypertension

We have demonstrated that angiotensin II increases mitochondrial localized O2− in cultured neurons

Adam J. Case; Jun Tian; Matthew C. Zimmerman

2016

Scholarcy highlights

  • Reactive oxygen species such as superoxide, hydrogen peroxide, and peroxynitrite have been implicated in the pathogenesis of angiotensin II-mediated hypertension
  • While the ROSA26 promoter is expressed in all cell types, minimal central nervous recombination has been observed in this model after tamoxifen administration, allowing for an efficient peripheral knockdown of manganese superoxide dismutase
  • Due to the observation that the MnSODL/L ROSA-Cre+/− mice did not elicit any change in MnSOD protein in the brain, we pursued the development of a mouse possessing MnSOD knock-down targeted to the brain subfornical organ; a blood-brain barrier deficient cardiovascular control nuclei known to be sensitive to circulating AngII
  • We have found that adenovirus-mediated over-expression of CuZnSOD in neurons leads to an accumulation of the enzyme in mitochondria, further supporting the idea that this enzyme plays a role in attenuating mitochondrial O2− in response to AngII
  • One possible explanation for this failure is that the antioxidants currently utilized do not target the appropriate cell type, subcellular location, or specific ROS produced that perpetuates the hypertension
  • After AngII had dissipated from the minipumps, no significant differences in mean arterial pressure were noted in either animal model
  • Our work here demonstrates that increased mitochondrial O2− in peripheral tissues or the brain is not sufficient to alter systemic hemodynamics, but increases in mitochondrial O2− in the brain SFO potentiate AngII-mediated hypertension. These findings advance the understanding of the specifics behind ROS in elevated blood pressure, and have elucidated a primary organ and subcellular target, as well as a specific ROS for therapeutic intervention in the treatment of hypertension associated with elevated levels of AngII
  • These findings advance the understanding of the specifics behind Reactive oxygen species in elevated blood pressure, and have elucidated a primary organ and subcellular target, as well as a specific ROS for therapeutic intervention in the treatment of hypertension associated with elevated levels of angiotensin II

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