Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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several genes containing the antioxidant response element (ARE) binding motif due

to the high similarity of consensus sequence between them [ 106 – 108 ]. Apart from

the classical antioxidant targets, Nrf2 regulates genes involved in anti-inflamma-

tory, Autophagy, Proteasomal pathway [ 109 – 111 ].

Nrf2 is regulated by several mechanisms. Under normal redox environment,

Nrf2 protein is sequestered in the cytoplasm by its inhibitor protein, Kelch-like

ECH associating protein 1 (Keap1) in a hinge and latch model and is targeted for

Cullin 3 /Ring-box 1 protein (Cul3/Rbx1)-based ubiquitination and degradation

[ 112 – 115 ]. However, upon conditions of oxidative stress or electrophilic stress,

Keap1 becomes oxidized at critical cysteine residues inducing a conformational

change resulting in dissociation of Nrf2 from Keap1. Subsequently, Nrf2 translo-

cates to the nucleus, partners with Maf and additional proteins, binds to cis-acting

ARE sequence and promotes gene transcription. In addition to the classical Keap1

based control, the stability of Nrf2 is regulated by E3 ubiquitin ligase based degra-

dation by Skp, Cullin, F-box/β-transducin repeat-containing protein (SCF/β-TrCP)

complex independent of Keap1 [ 116 ]. Particularly, this has been shown to be medi-

ated by glycogen synthase kinase 3 (GSK-3) that phosphorylates specific serine

residues in the Neh6 domain of Nrf2 corresponding to the β-TrCP recognition motif

and directs it for degradation [ 116 ]. Further, Nrf2 activation may occur following its

phosphorylation by several kinases such as mitogen activated protein kinase, phos-

phatidylinositol 3-kinase, protein kinase C, and protein kinase RNA-like endoplas-

mic reticulum kinase (PERK) [ 117 , 118 ]. In a feed-forward manner, Nrf2 protein

transcriptionally regulates its own gene expression by binding to two ARE-like

motifs that are present in its promoter region [ 119 ]. Nrf2 is also regulated by the

epigenetics and miRNA-based post-transcriptional mechanisms [ 120 , 121 ].

Nrf2 possess an evolutionarily conserved role in protection against OS [ 122 ]. Of

note, the intensive function and relatively minimal and slow rate of replacement of

Fig. 13.2 Redox-dependent regulation of cardiac function. Oxidant to antioxidant balance is cru-
cial for optimal cardiac function. The decrease in either oxidants or antioxidants leads to ineffec-
tive cardiac function. Abnormal increase of either will result in supra-normal (pathological)
function and heart failure

13 Cardiac Agingfi– Bene ts offiExercise, Nrf2 Activation andfiAntioxidant Signaling