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.

Molecular Basis of the Brain Renin Angiotensin System in Cardiovascular and Neurologic Disorders: Uncovering a Key Role for the Astroglial Angiotensin Type 1 Receptor AT1R

“…At a molecular level, several mechanisms such as endoplasmic reticulum stress, mitochondrial dysfunction, and redoxsensitive transcriptional factors have all been attributed to brain-derived Ang II promoting neurogenic hypertension and baroreflex impairment (Nautiyal et al, 2013;Coble et al, 2015;Young and Davisson, 2015;Case et al, 2017). An increase in reactive oxygen species (ROS) levels in the brainstem cardioregulatory centers is a crucial step by which Ang II is able to augment multiple cardiovascular parameters such as sympathetic tone, heart rate, and water intake (Zimmerman et al, 2002(Zimmerman et al, , 2004Nozoe et al, 2008;Chan and Chan, 2012).…”

Biosensors for spatiotemporal detection of reactive oxygen species in cells and tissues

“…Tissuespecific promoters restrict gene expression, gene disruption, or knockdown (102,169). Local injection of appropriate viruses allows site-specific transduction (24) while new viral expression systems are developed for improved cellular specificity (82). The whole arsenal for tissue-specific genetic engineering is available for site-specific detection with all types of optogenetic indicators (169).…”

New insights into arterial baroreflex function during acute exercise: role of central angiotensin II

“…Exaggerated haemodynamic responses during exercise may be caused by excess free radical production, and previous animal literature suggests centrally acting angiotensin II (Ang II) may play a role in the excess free radical production, and in the resetting of the arterial baroreflex (Case et al . ). However, these mechanisms have not been elucidated in humans.…”

“…Ang II‐dependent increases in sympathetic outflow and BP can be attenuated by O 2 − scavenging targeted to the brain or central AT 1 receptor blockade (Case et al . ). Further, these effects are exacerbated by a knockdown of anti‐oxidant enzymes in specific brain structures (e.g.…”

“…superoxide dismutase knockdown in the subfornical organ), demonstrating a critical role of downstream ROS (Case et al . ). A greater elevation in plasma Ang II during maximal exercise is associated with greater peak systolic and diastolic BP responses in normotensive middle‐aged adults (Shim et al .…”