The Role of Nrf2 in the Cardiovascular System and Atherosclerosis

Determination of Complex Formation between Drosophila Nrf2 and GATA4 Factors at Selective Chromatin Loci Demonstrates Transcription Coactivation

“…Given the role of both Nrf2 and GATA4 in cardiac development, our study also hints at potential crosstalk between classic oxidative/xenobiotic response signaling and the transcription-regulatory network controlling cardiac development. It is well established that Nrf2 can protect the cardiovascular system through the regulation of redox hemostasis in blood vessels, blood cells, and the myocardium [ 54 ]. The pathogenic roles of Nrf2 in cardiovascular diseases, including atherosclerosis and heart failure, have also been revealed by several studies [ 10 , 54 ].…”

“…It is well established that Nrf2 can protect the cardiovascular system through the regulation of redox hemostasis in blood vessels, blood cells, and the myocardium [ 54 ]. The pathogenic roles of Nrf2 in cardiovascular diseases, including atherosclerosis and heart failure, have also been revealed by several studies [ 10 , 54 ]. Despite the roles of Nrf2 in cardiovascular specific cell protection, the function of Nrf2 in cardiovascular development remains unclear.…”

Induction of Cardiac Pathology: Endogenous versus Exogenous Nrf2 Upregulation

“…Nrf2 is a basic leucine zipper (bZIP) transcription factor on chromosome 2 in humans, comprised of a common, conserved Cap ‘n’ Collar (CNC) motif of 43 amino acids close to the DNA binding domain [ 1 ]. NRF2 consists of 6 exons, encoding 7 Nrf2-ECH homology (Neh) domains, and generates a 67.8 kDa protein from a 605 aa sequence and 2859 bp mRNA strand [ 2 , 3 , 4 ]. These Neh domains are specific for protein–protein interactions, especially regulatory, degradation, and translocation proteins ( Table 1 ).…”

“…Keap1 is a 70 kDa protein with a long 12.7 h half-life that localizes to the cytoplasm [ 7 ]. It is comprised of a BTB (Broad, Tramtrack and Bric-a-brac region) domain and Kelch repeats that bind directly to Nrf2-Neh2 in a 6-blade, β -propeller configuration that permits dimerization of 2 Keap1 molecules to each Nrf2 molecule in a hinged-capture structure with ETGE and DLG regions on the C-terminal end of Nrf2 to act as pivoting attachment points to Keap1 [ 4 , 7 ]. Under basal conditions, the conformational change induced by the Keap1-Nrf2 complex, NEDD8, and ubiquitin E3 ligase CUL3 exposes lysine residues within Neh2 (and possibly Neh6) to attack by a K48 polyubiquitination complex consisting of CUL3 and ring ligase RBX1 that bind to the BTB region of Keap1 before activation [ 7 , 14 ].…”

“…The binding affinity of Kesp1 to Nrf2 has been experimentally reported as KD 20 nM and, as such, spontaneous dissociation is unlikely [ 15 ]. However, 27 cysteine residues of Keap1 are vulnerable to attack by endogenous and exogenous reactive species, particularly C151 in the homodimerizing BTB region, that dissociate the CUL3 ubiquitin adaptor from the complex, allowing Nrf2 to escape polyubiquitination and begin translocation to the nucleus [ 4 , 16 , 17 ]. The p62/mTORC-1 dependent machinery, activated by autophagy, can also repress Keap1 by degrading it in the autophagic pathway [ 18 , 19 ].…”