Overexpression of Nrf2 Targeting Glutamatergic Neurons in the RVLM Ameliorates Sympathetic Regulation in Mice With Chronic Heart Failure

Nrf2 is a key transcription factor that regulates redox status by up‐regulating a broad array of antioxidant genes. Previous data from our laboratory demonstrated that enhanced oxidative stress in the RVLM contributed to the sympatho‐excitation in rabbits with chronic heart failure (HF). Accordingly, we hypothesized that overexpression of Nrf2 in the RVLM will suppress sympathetic tone via enhancing antioxidant defense. Thirty C57BL/6 mice were randomized into four groups: Sham‐lentiviral GFP (7); Sham‐lentiviral GFP Nrf2 (7); HF‐lenti GFP (8); and HF‐lenti GFP Nrf2 (8). HF was induced by coronary artery ligation while sham surgery was used as the control. Nrf2 was upregulated selectively in glutamatergic neurons of RVLM by microinjection of Ca 2+ /calmodulin‐dependent protein kinase‐II (CaMKII) promoter‐driven Nrf2 lentivirus and a corresponding GFP vector was used as the control. We found that (1) Nrf2 protein was significantly downregulated in the RVLM of HF mice, which was restored by Nrf2 gene transfer. (2) The increased urinary NE excretion in HF was attenuated by Nrf2 overexpression (Sham‐GFP: 575.2 ± 265.0, HF‐GFP, 1119.6 ± 270.5, HF‐Nrf2: 812.1 ± 133.0 ng/24hr. *p < 0.05, n = 7–8/group). (3) Radio telemetry experiments (in the conscious state) showed that Nrf2 overexpression enhanced spontaneous baroreflex gain and increased PE induced bradycardia in HF (Decline of HR: Sham‐GFP: −53.7 ± 4.8; HF−GFP: −4.7 ± 5.1; HF‐Nrf2: −25.1 ± 2.3 % of Max. *P < 0.05 HF‐GFP vs Sham‐GFP and HF‐Nrf2 vs HF‐GFP, n = 7–8/group), and attenuated stress‐induced pressor responses in both Sham (surgical‐stress: 101.5 ± 5.9 vs 129.7 ± 7.2 mmHg, restraint‐stress: 118.8 ± 6.8 vs 151.5 ± 8.2 mmHg. *P < 0.05, n = 7/group) and HF mice (surgery‐stress: 111.06 ± 5.87 vs 135.83 ± 7.24 mmHg, restrain‐stress: 102.8 ± 8.2 vs 119.2 ± 6.3 mmHg. *P < 0.05, n = 8/group). No difference in baseline blood pressure and heart rate were observed among these groups. (4) Acute experiments (in the anesthetized state) revealed a decrease in basal renal sympathetic nerve activity (Sham‐GFP: 28.6 ± 5.2, HF‐GFP: 64.7 ± 8.3, HF‐Nrf2: 44.0 ± 6.5 % of Max. *P < 0.05 HF‐GFP vs Sham‐GFP and HF‐Nrf2 vs HF‐GFP, n = 7–8/group) and improvement of baroreflex sensitivity (Maximal Gain: Sham‐GFP: 2.9 ± 0.1, HF‐GFP: 1.1 ± 0.2, HF‐Nrf2: 1.8 ± 0.3 % of mmHg. **p < 0.01 HF‐GFP vs Sham‐GFP; *P < 0.05 HF‐Nrf2 vs HF‐GFP, n = 7–8/group) in HF mice by Nrf2 overexpression. Based on the above data, we conclude that upregulating Nrf2 expression in glutamatergic neurons of the RVLM ameliorates sympathetic regulation in mice with HF and attenuates stress‐induced pressor responses in both sham and HF mice. Support or Funding Information Supported by NIH grant P01‐HL62222 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .