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

ABSTRACT: Angiotensin II (AngII) elicits the production of superoxide (O₂^•-) from mitochondria in numerous cell types within peripheral organs and in the brain suggesting a role for mitochondrial-produced O₂^•- in the pathogenesis of hypertension. However, it remains unclear if mitochondrial O₂^•- is causal in the development of AngII-induced hypertension, or if mitochondrial O₂^•- in the absence of elevated AngII is sufficient to increase blood pressure. Further, the tissue specific (i.e. central versus peripheral) redox regulation of AngII hypertension remains elusive. Herein, we hypothesized that increased mitochondrial O₂^•- in the absence of pro-hypertensive stimuli, such as AngII, elevates baseline systemic mean arterial pressure (MAP), and that AngII-mediated hypertension is exacerbated in animals with increased mitochondrial O₂^•- levels. To address this hypothesis, we generated novel inducible knock-down mouse models of manganese superoxide dismutase (MnSOD), the O₂^•- scavenging antioxidant enzyme specifically localized to mitochondria, targeted to either the brain subfornical organ (SFO) or peripheral tissues. Contrary to our hypothesis, knock-down of MnSOD either in the SFO or in peripheral tissues was not sufficient to alter baseline systemic MAP. Interestingly, when mice were challenged with chronic, peripheral infusion of AngII, only the MnSOD knock-down confined to the SFO, and not the periphery, demonstrated an increased sensitization and potentiated hypertension. In complementary experiments, over-expressing MnSOD in the SFO significantly decreased blood pressure in response to chronic AngII. Overall, these studies indicate that mitochondrial O₂^•- in the brain SFO works in concert with other AngII-dependent factors to drive an increase in MAP, as elevated mitochondrial O₂^•- alone, either in the SFO or peripheral tissues, failed to raise baseline blood pressure.

SUBMITTER: Case AJ

PROVIDER: S-EPMC5124355 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Case Adam J AJ Tian Jun J Zimmerman Matthew C MC

Redox biology 20161120

Angiotensin II (AngII) elicits the production of superoxide (O2•-) from mitochondria in numerous cell types within peripheral organs and in the brain suggesting a role for mitochondrial-produced O2•- in the pathogenesis of hypertension. However, it remains unclear if mitochondrial O2•- is causal in the development of AngII-induced hypertension, or if mitochondrial O2•- in the absence of elevated AngII is suff ...[more]

PMID: 27889641

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Project description:AimsAngiotensin II (AngII)-induced superoxide (O2(•-)) production by the NADPH oxidases and mitochondria has been implicated in the pathogenesis of endothelial dysfunction and hypertension. In this work, we investigated the specific molecular mechanisms responsible for the stimulation of mitochondrial O2(•-) and its downstream targets using cultured human aortic endothelial cells and a mouse model of AngII-induced hypertension.ResultsWestern blot analysis showed that Nox2 and Nox4 were present in the cytoplasm but not in the mitochondria. Depletion of Nox2, but not Nox1, Nox4, or Nox5, using siRNA inhibits AngII-induced O2(•-) production in both mitochondria and cytoplasm. Nox2 depletion in gp91phox knockout mice inhibited AngII-induced cellular and mitochondrial O2(•-) and attenuated hypertension. Inhibition of mitochondrial reverse electron transfer with malonate, malate, or rotenone attenuated AngII-induced cytoplasmic and mitochondrial O2(•-) production. Inhibition of the mitochondrial ATP-sensitive potassium channel (mitoK(+)ATP) with 5-hydroxydecanoic acid or specific PKCɛ peptide antagonist (EAVSLKPT) reduced AngII-induced H2O2 in isolated mitochondria and diminished cytoplasmic O2(•-). The mitoK(+)ATP agonist diazoxide increased mitochondrial O2(•-), cytoplasmic c-Src phosphorylation and cytoplasmic O2(•-) suggesting feed-forward regulation of cellular O2(•-) by mitochondrial reactive oxygen species (ROS). Treatment of AngII-infused mice with malate reduced blood pressure and enhanced the antihypertensive effect of mitoTEMPO. Mitochondria-targeted H2O2 scavenger mitoEbselen attenuated redox-dependent c-Src and inhibited AngII-induced cellular O2(•-), diminished aortic H2O2, and reduced blood pressure in hypertensive mice.Innovation and conclusionsThese studies show that Nox2 stimulates mitochondrial ROS by activating reverse electron transfer and both mitochondrial O2(•-) and reverse electron transfer may represent new pharmacological targets for the treatment of hypertension.

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

Publications

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

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