Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C009

Oral Communications

Modulation of Sympathetic Tone in Heart Failure: a Role for neuronal Nrf2

J. Shanks1, L. Gao1, I. Zucker1

1. Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, United States.

Nrf2 is a key transcription factor involved in modulating redox signaling by regulating the expression of a number of antioxidant genes. It is known that both sympathetic hyperactivity and increased oxidative signaling are hallmarks of chronic heart failure (HF). Previous data from our group has shown that enhanced oxidative signaling in the RVLM contributed to the sympatho-excitation in rabbits with HF. We hypothesized that Nrf2 expression would be downregulated in sympathetic neural tissue in HF, and that overexpression of Nrf2 in the RVLM would suppress HF associated increased sympathetic tone. To test the role of RVLM Nrf2 over expression in HF 30 C57BL/6 male mice were randomized into 4 groups : Sham-Lenti GFP (n = 7); Sham-Lenti GFP Nrf2 (n = 7); HF-Lenti GFP (n = 8); and HF-Lenti GFP Nrf2 (n = 8). HF was induced by coronary artery ligation (under 2% isoflurane), or sham surgery as control. Nrf2 overexpression was selectively targeted to glutamatergic neurons of the RVLM by utilizing a Ca2+/calmodulin-dependent protein kinase-II (CaMKII) promoter to drive Nrf2 expression, a corresponding GFP vector was used as control. We found that Nrf2 protein was significantly downregulated in the RVLM of HF mice, which was restored by Nrf2 gene transfer. That 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). 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). Moreover, no difference in baseline blood pressure and heart rate were observed between groups. Acute experiments (2 % isoflurane) revealed a decrease in basal renal sympathetic nerve activity in heart failure with Nrf2 over expression in the RVLM (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). From this data we conclude that upregulating Nrf2 expression in glutamatergic neurons of the RVLM reduces sympathetic activity in mice with HF. In addition to the mouse model we observe a reduction in Nrf2, and its downstream target NQO1 in the stellate ganglia of HF rats (10 weeks post coronary artery ligation - 2% isoflurane, n = 5, sham and HF), reduction in stellate ganglia Nrf2 is correlated with infarct size and ejection fraction. This indicates that Nrf2 may be globally reduced within sympathetic tissue in HF and could open the potential for future therapeutic targets. The role of stellate ganglia Nrf2 in cardiac sympathetic drive and redox signaling in HF remain to be determined.

Where applicable, experiments conform with Society ethical requirements