Abstract 120: Increased Mitochondrial Superoxide in the Brain, but not Periphery, Sensitizes Mice to Angiotensin II-Mediated Hypertension
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Mitochondrial superoxide (O 2[[Unable to Display Character: ●]]- ) is a critical signaling intermediate in angiotensin II (AngII)-dependent hypertension. However, it remains unknown if increased mitochondrial O 2[[Unable to Display Character: ●]]- flux in the absence of hypertensive stimuli is sufficient to affect blood pressure. We hypothesized that elevated levels of systemic mitochondrial O 2[[Unable to Display Character: ●]]- leads to increased blood pressure and exacerbates AngII-induced hypertension. To test this, we utilized a conditional mouse model of manganese superoxide dismutase knock-out (MnSOD lox/lox ), which we have shown amplifies steady-state mitochondrial O 2[[Unable to Display Character: ●]]- levels in all cell types examined. When combining the MnSOD lox/lox mouse with a tamoxifen-inducible cre recombinase expressed by the systemic ROSA26 promoter, MnSOD was knocked-down (30-98%, p<0.05) in peripheral organs after intraperitoneal tamoxifen administration. However, no changes in MnSOD protein levels were observed in the brain. Interestingly, mean arterial pressure (MAP) and heart rate were unaffected by the loss of MnSOD in these peripheral tissues, and moreover, upon subcutaneous infusion with AngII (400 ng/kg/min) both wild-type and MnSOD knock-down mice exhibited a similar increase in MAP. Due to these unexpected results, we examined the role of elevated mitochondrial O 2[[Unable to Display Character: ●]]- levels specifically in the brain subfornical organ (SFO) by targeting the loss of MnSOD to this critical AngII-sensitive region. We observed a 60% decrease of MnSOD (p<0.05) with concomitant increase in mitochondrial O 2[[Unable to Display Character: ●]]- , as measured by MitoSox Red fluorescence, in the SFO following adenovirus-mediated gene transfer of cre recombinase to the SFO in MnSOD lox/lox mice. Intriguingly, these mice demonstrated no change in baseline MAP (92.8 0.4 mmHg in knock-down vs. 93.1 0.4 mmHg in control mice), but did show a significant elevation in MAP upon peripheral AngII infusion (MAP max = 137.8 2.7 mmHg in knock-down vs. 128.3 3.3 mmHg in control mice, p<0.05). Taken together, our data suggest that increased mitochondrial O 2[[Unable to Display Character: ●]]- in the absence of hypertensive stimuli is not sufficient to alter baseline hemodynamics, but dysregulation of mitochondrial redox status in the SFO may be a predisposition to increased responsiveness to hypertensive stimuli, such as AngII.
