Nrf2 at the heart of oxidative stress and cardiac protection

Abstract

The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.

Cyclovirobuxine D protects against diabetic cardiomyopathy by activating Nrf2-mediated antioxidant responses

“…As a major transcription factor of cellular antioxidant response, accumulated evidence has suggested that activation of Nrf2 may have potential therapeutic in multiple cardiovascular diseases, such as heart failure, diabetes, diabetic nephropathy, and DCM [39][40][41][42] . At present, diabetes caused a significant down-regulation of Nrf2 and downstream molecules such as NQO-1 and Prdx-1, and CVB-D alleviated the expression of these proteins both in vivo and in vitro.…”

“…As oxidative stress is a common pathogenesis of metabolic diseases, some pharmacological activators of Nrf2, such as mitoquinone 13,14 , bardoxolone methyl 15 , and sulforaphane 16 , have shown beneficial therapeutic potential. However, off-target side effects also were observed because of the unselective activity of Nrf2 [17][18][19] . Therefore, it is important for exploring the novel promising agent targeted Nrf2 agonist for the DCM.…”

Bcl6 knockdown aggravates hypoxia injury in cardiomyocytes via the P38 pathway

“…Generally, p38 is activated by, and contributes to, lethal ischemic injury (Martin et al, ). Many P38 inhibitors have proved beneficial in animal models and pre‐clinical studies (Newby et al, ; Chen and Maltagliati, ). Previous studies have demonstrated that P38 was activated in Bcl6 deficient mice spermatocytes (Kojima et al, ).…”

Inhibition of miR-153 ameliorates ischemia/reperfusion-induced cardiomyocytes apoptosis by regulating Nrf2/HO-1 signaling in rats

“…Nrf2 is a transcription factor that plays a major role in the dynamic regulation of a network of antioxidant and cytoprotective genes. Nrf2 is indicated in playing a role in different aspects of cardiovascular disease [46][47][48]. Applied the same surgical strategy, we delivered siRNA targeting Nrf2 into the heart of rat using adenovirus injection.…”