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Review
. 2021 Nov 3;22(21):11939.
doi: 10.3390/ijms222111939.

The Antioxidant Transcription Factor Nrf2 in Cardiac Ischemia-Reperfusion Injury

Ana Mata  1   2 , Susana Cadenas  1   2
Affiliations
Review

The Antioxidant Transcription Factor Nrf2 in Cardiac Ischemia-Reperfusion Injury

Ana Mata et al. Int J Mol Sci. .

Abstract

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that controls cellular defense responses against toxic and oxidative stress by modulating the expression of genes involved in antioxidant response and drug detoxification. In addition to maintaining redox homeostasis, Nrf2 is also involved in various cellular processes including metabolism and inflammation. Nrf2 activity is tightly regulated at the transcriptional, post-transcriptional and post-translational levels, which allows cells to quickly respond to pathological stress. In the present review, we describe the molecular mechanisms underlying the transcriptional regulation of Nrf2. We also focus on the impact of Nrf2 in cardiac ischemia-reperfusion injury, a condition that stimulates the overproduction of reactive oxygen species. Finally, we analyze the protective effect of several natural and synthetic compounds that induce Nrf2 activation and protect against ischemia-reperfusion injury in the heart and other organs, and their potential clinical application.

Keywords: Nrf2 activators; cardioprotection; ischemia–reperfusion injury; ischemic conditioning; oxidative stress; reactive oxygen species; redox homeostasis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of human Nrf2 and Keap1. The high-affinity ETGE and low-affinity DLG motifs in the Neh2 domain of Nrf2 are bound by the Kelch domain of Keap1 for Nrf2 ubiquitination and degradation. ARE, antioxidant response element; BTB, broad-complex, tramtrack and bric-à-brac domain; CTR, C-terminal region; DGR or Kelch, double glycine repeat domain; IVR, intervening region; Neh, Nrf2-erythroid-derived CNC homology (ECH) domain; NTR, N-terminal region.
Figure 2
Figure 2
Regulation of Nrf2 transcriptional activity by Keap1. Nrf2 activity and hence the expression of its target genes is maintained at low levels by Keap1 under normal homeostatic conditions, but increases rapidly in response to redox and electrophilic stressors as well as by stimulation by growth factors. Cys151 is required for triggering Nrf2 signaling by activating agents, and Cys273 and Cys288 are functionally important for the sensing of inducers [56]. The biological effects of Nrf2 are exerted through its ability to mediate the induction of genes containing an antioxidant response element (ARE) in their promoter region upon exposure to a broad spectrum of oxidants and eletrophiles.
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