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.
Highlights
In addition to producing cellular energy in the form of ATP from fuel oxidation, mitochondria are an important source of reactive oxygen species (ROS), which play a central role in redox signaling and contribute to oxidative damage across a range of pathologies [1,2,3]
In response to different activation stimuli, nuclear factor erythroid 2-related factor 2 (Nrf2) translocates from the cytoplasm to the nucleus, where it activates the transcription of its downstream targets by binding to a cis-acting enhancer with a core nucleotide sequence of 5 -TGACNNNGC-3 where N is any nucleotide, termed the antioxidant response element (ARE) or the electrophile response element (EpRE) [11,12]
The Nrf2/Kelch-like erythroid-derived CNC homology (ECH) associated protein 1 (Keap1) pathway plays a key role in the defense against oxidative stress and the maintenance of redox homeostasis
Summary
In addition to producing cellular energy in the form of ATP from fuel oxidation, mitochondria are an important source of reactive oxygen species (ROS), which play a central role in redox signaling and contribute to oxidative damage across a range of pathologies [1,2,3]. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of the cellular stress response. In line with the focus of the present review, there is substantial evidence for a protective role of Nrf in cardiovascular diseases, including atherosclerosis, ischemia–reperfusion (IR) injury, cardiac hypertrophy, heart failure and diabetes (reviewed in [16]), some harmful effects have been reported [17,18,19]. Nrf activation protects the heart along with other organs from the damage that ensues upon restoration of blood flow to an ischemic tissue, which is known as IR injury. We examine the role of Nrf in cellular redox homeostasis and the regulation of its transcriptional activity. We review studies on the protection offered by the aforementioned compounds against cardiac IR injury
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