Nrf2-Mediated Antioxidant Defense and Thyroid Hormone Signaling: A Focus on Cardioprotective Effects

Abstract

Thyroid hormones (TH) perform a plethora of actions in numerous tissues and induce an overall increase in metabolism, with an augmentation in energy demand and oxygen expenditure. Oxidants are required for normal thyroid-cell proliferation, as well as for the synthesis of the main hormones secreted by the thyroid gland, triiodothyronine (T3) and thyroxine (T4). However, an uncontrolled excess of oxidants can cause oxidative stress, a major trigger in the pathogenesis of a broad spectrum of diseases, including inflammation and cancer. In particular, oxidative stress is implicated in both hypo- and hyper-thyroid diseases. Furthermore, it is important for the TH system to rely on efficient antioxidant defense, to maintain balance, despite sustained tissue exposure to oxidants. One of the main endogenous antioxidant responses is the pathway centered on the nuclear factor erythroid 2-related factor (Nrf2). The aim of the present review is to explore the multiple links between Nrf2-related pathways and various TH-associated conditions. The main aspect of TH signaling is described and the role of Nrf2 in oxidant-antioxidant homeostasis in the TH system is evaluated. Next, the antioxidant function of Nrf2 associated with oxidative stress induced by TH pathological excess is discussed and, subsequently, particular attention is given to the cardioprotective role of TH, which also acts through the mediation of Nrf2. In conclusion, the interaction between Nrf2 and most common natural antioxidant agents in altered states of TH is briefly evaluated.

Keywords: Nrf2; antioxidants; cardioprotection; oxidative stress; thyroid hormones.

Figure 1

Representation of genomic and non-genomic actions of TH in the cell. Genomic actions begin at the plasma membrane and THs enter the cell through specific TH transporters. Once in the cell, T4 is converted to T3 by D1 and D2 deiodinases and T3 enters the nucleus, where it binds to specific receptors, which mediate the interaction with the DNA. Non-genomic mechanisms require the mediation of integrin ανβ3, which has a higher binding affinity for T4 than T3. Once in the cell, THs activate several MAPK-mediated signaling pathways. At the plasma-membrane level, TH regulate glucose transporter, Na⁺/K⁺-ATPase, Na⁺/H⁺-exchanger, Ca²⁺-ATPase, and the Na+-sensitive amino-acid transporter. TH: thyroid hormones; T3: triiodothyronine; T4: thyroxine; TRs: thyroid-hormone receptors; TRE: thyroid-responsive elements; DIO1: deiodinase 1; DIO2: deiodinase 2; STATs: signal transducer and activator of transcription 1α and 3; ERα: estrogen receptor α.

Figure 2

Representation of Nrf2–ARE pathway activation by oxidants. In normal conditions, Keap1 acts as an adaptor targeting Nrf2 and inducing proteasomal degradation. In presence of excess oxidant stimuli, Keap1’s stabilizing function is inactivated and Nrf2 accumulates in the nucleus. At the nuclear level, Nrf2 acts as a transcription factor interacting with the ARE sequences in the promoters of numerous target genes encoding antioxidant enzymes and other cytoprotective molecules.

Figure 3

Nrf2 signaling in different pathological contexts.

Figure 4

Schematic representation of main cardiac phenotypes associated with Nrf2 overexpression or lack of expression (Nrf-KO mice).