Selective Nrf2 Overexpression in the RVLM ameliorates Obesity-induced Sympathoexcitation

The rostral part of the ventrolateral medulla (RVLM) in the brainstem is an important region responsible for both the resting levels and the reflex control of sympathetic nerve activity (SNA). Oxidative stress-induced hyperactivation of the glutamatergic neurons in the RVLM has been associated with increases in SNA. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor ubiquitously expressed in all cell types and regulates the expression of several antioxidant and anti-inflammatory genes. Previous studies from our lab have demonstrated that obesity-induced sympathoexcitation was associated with Nrf2 dysfunction in the RVLM. Based on this, we hypothesized that Nrf2 overexpression at the level of the RVLM would reverse obesity-induced sympathoexcitation. To address this hypothesis, we selectively overexpressed Nrf2 at the level of the RVLM using a Nrf2 lentiviral vector (HIV-CamKIIa-GFP-Nrf2). This vector drives Nrf2 gene overexpression under the control of CamKIIa promoter that specifically targets the excitatory glutamatergic neurons. A control GFP vector (CamKIIa-GFP-virus) was used in the sham surgeries. For this experiment, two-month-old C57BL/6J mice (n=34, both sexes) were fed a high-fat diet (HFD; 60kcal% fat) or a chow diet (Control; 10kcal% fat) for 4-6 months. The animals were then subdivided into four subgroups (each group included an equal number of animals of both sexes): Chow + Control GFP lentiviral vector, HFD + Control GFP lentiviral vector, Chow + Nrf2 lentiviral vector, HFD + Nrf2 lentiviral vector. After 16 weeks of dietary treatment, the animals were microinjected with either control GFP or Nrf2 lentiviral vector in the RVLM. Two weeks after the microinjection surgery, radiotelemeters were implanted in the mice, and hemodynamic parameters were measured. Hexamethonium, a ganglionic blocker was injected into the animals to measure the drop in MAP, which is an indirect measurement of the whole-body SNA. Major findings from this study include a) As expected, HFD treatment increased systolic blood pressure (SBP), and mean arterial pressure (MAP). Nrf2 overexpression in the RVLM reversed SBP but not MAP in HFD mice when compared to control GFP vector group. b) Consistent with our earlier findings, animals fed with HFD diet showed a significant drop in blood pressure after hexamethonium injection compared to the control animals indicating HFD-induced increase in SNA. Nrf2 overexpression was also able to reduce the drop in MAP in response to hexamethonium in the HFD animals compared to control GFP vector group, suggesting Nrf2 overexpression attenuated obesity-mediated sympathoexcitation. These results indicate that Nrf2 upregulation in the RVLM can be a potential therapeutic option for obesity-induced increase in blood pressure and sympathoexcitation. Supported by: National Heart, Blood and Lung Institute grant R15HL148844 and American Heart Association Institutional Research Enhancement Award - 959725 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.