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

Angiotensin II (AngII) elicits the production of superoxide (O-2(center dot-))from mitochondria in numerous cell types within peripheral organs and in the brain suggesting a role for mitochondrial-produced O-2(center dot-) in the pathogenesis of hypertension. However, it remains unclear if mitochondrial O-2(center dot-) is causal in the development of AngII-induced hypertension, or if mitochondrial O-2(center dot-) 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 O-2(center dot-) 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 O-2(center dot-) levels. To address this hypothesis, we generated novel inducible knock-down mouse models of manganese superoxide dismutase (MnSOD), the O-2(center dot-) 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 O-2(center dot-) in the brain SFO works in concert with other AngII-dependent factors to drive an increase in MAP, as elevated mitochondrial O-2(center dot-) alone, either in the SFO or peripheral tissues, failed to raise baseline blood pressure.