Sympathomodulation in heart failure: A role for stellate ganglia Nrf2

Abstract

Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is a key transcription factor involved in modulating redox signalling by regulating the expression of a number of antioxidant genes. It is known that both sympathetic hyperactivity and increased oxidative signalling are hallmarks of chronic heart failure (HF). Previous data from our group have shown that site selective deletion of Nrf2 in the rostral ventrolateral medulla (RVLM) increases blood pressure, reduces baroreflex sensitivity and increases renal sympathetic nerve activity (RSNA) in normotensive mice. Moreover, Nrf2 expression is downregulated in the RVLM of HF mice, where its selective viral up regulation improves baroreflex sensitivity and reduces sympathetic tone. In this study we hypothesized that Nrf2 expression is downregulated in all sympathetic neural tissue in HF, and that selective overexpression of Nrf2 in the stellate ganglia would suppress cardiac sympatho‐hyperactivity and arrhythmogenesis in HF. Heart failure was induced by coronary artery ligation in both mice and rats. Terminal experiments were performed 6 weeks post MI. Heart failure was confirmed by echocardiography. Nrf2 protein and message expression were determined by western blot and rt‐PCR, respectively. Markers of oxidative stress within the stellate were determined using a variety of immunofluorescent techniques. Acute terminal experiments (2 % isoflurane) in rats, determined haemodynamic changes to stellate stimulation. Expression of Nrf2 protein and message was significantly down regulated within the stellate ganglia of both male and female mice (Nrf2 Protein: Male‐Sham, 0.65 ± 0.08 (n = 10), Male‐HF, 0.29 ± 0.13 (n = 9), p < 0.01. Female‐Sham, 0.53 ± 0.05 (n = 3), Female‐HF, 0.25 ± 0.04 (n = 3), ratio Nrf2/GAPDH). Nrf2 mRNA: Male‐Sham, 0.98 ± 0.03 (n = 2), Male‐HF, 0.49 ± 0.55 (n = 3), p < 0.05). Increased markers of redox signalling were seen within the stellate ganglia of HF mice, including increased labelling for 3‐Nitrosylation (3‐NT), 4 Hydroxynonenal, 8‐OHdG, and DHE as a marker of superoxide production. We also observed 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), a reduction in stellate Nrf2 was correlated with infarct size and ejection fraction. Within the HF group we observed increased haemodynamic changes to stellate stimulation in anaesthetized rats. These data suggest that oxidative signalling is increased and Nrf2 reduced within the stellate ganglia in HF and could open the potential for future therapeutic targets. Upregulation of Nrf2 in the stellate ganglia and the role of stellate ganglia Nrf2 in cardiac sympathetic drive and redox signalling in HF remain to be determined.Support or Funding InformationWork done with support of the NIH (PO‐1 HL62222) and AHA (18POST34030046).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.