Nrf2 and autonomic dysregulation in chronic heart failure and hypertension

Abstract

Redox imbalance plays essential role in the pathogenesis of cardiovascular diseases. Chronic heart failure (CHF) and hypertension are associated with central oxidative stress, which is partly mediated by the downregulation of antioxidant enzymes in the central autonomic neurons that regulate sympathetic outflow, resulting in sympathoexcitation. Antioxidant proteins are partially regulated by the transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2). Downregulation of Nrf2 is key to disrupting central redox homeostasis and mediating sympathetic nerve activity in the setting of Chronic heart failure and hypertension. Nrf2, in turn, is regulated by various mechanisms, such as extracellular vesicle-enriched microRNAs derived from several cell types, including heart and skeletal muscle. In this review, we discuss the role of Nrf2 in regulating oxidative stress in the brain and its impact on sympathoexcitation in Chronic heart failure and hypertension. Importantly, we also discuss interorgan communication via extracellular vesicle pathways that mediate central redox imbalance through Nrf2 signaling.

Keywords: heart failure; hypertension; oxidative stress; redox homeostasis; sympathoexcitation.

FIGURE 1

Schematic overview of Nrf2 signaling pathway–Under basal condition, Nrf2 is tethered to Keap-1, resulting in polyubiquitination and proteasomal degradation of Nrf2. Under oxidative stress condition, cysteine residues of Keap-1 are oxidized, resulting in a conformational change and translocation of Nrf2 into nucleus, where it binds to ARE to increase the transcription of antioxidant enzymes. Additionally, varieties of phytochemicals can activate Nrf2 through Keap-1 independent mechanism via phosphorylation by different kinases.

FIGURE 2

Schematic representation of the impact of Nrf2 gene deletion selectively in the RVLM of normal mice on sympathetic outflow and blood pressure (Based on the findings of Gao et al.) (Gao et al., 2017). Nrf2 gene deletion in the RVLM increases blood pressure, augments sympathetic outflow, and impairs baroreflex function.

FIGURE 3

Schematic representation of the impact of Nrf2 upregulation in the RVLM on sympathetic outflow in CHF state using either C57BL/6 or Keap-1^f/f mice (Based on the findings of Ma et al.) (Ma et al., 2019). In C57BL/6, Nrf2 was overexpressed in the RVLM using HIV-CamKII-Nrf2 Lenti virus, whereas in Keap-1^f/f mice, Nrf2 was overexpressed in the RVLM using Lenti-Cre virus. Nrf2 upregulation selectively in the RVLM ameliorates sympathoexcitation in CHF mice.

FIGURE 4

Schematic representation of heart-brain communication via EVs enriched miRNA that modulate Nrf2 expression in the RVLM (Modified from Tian et al.) (Tian et al., 2022).