Abstract
Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) is a critical transcription factor that regulates the expression of over 1000 genes in the cell under normal and stressed conditions. These transcripts can be categorized into different groups with distinct functions, including antioxidative defense, detoxification, inflammatory responses, transcription factors, proteasomal and autophagic degradation, and metabolism. Nevertheless, Nrf2 has been historically considered as a crucial regulator of antioxidant defense to protect against various insult-induced organ damage and has evolved as a promising drug target for the treatment of human diseases, such as heart failure. However, burgeoning evidence has revealed a detrimental role of Nrf2 in cardiac pathological remodeling and dysfunction toward heart failure. In this mini-review, we outline recent advances in structural features of Nrf2 and regulation of Nrf2 activity and discuss the emerging dark side of Nrf2 in the heart as well as the potential mechanisms of Nrf2-mediated myocardial damage and dysfunction.
Highlights
Heart failure is defined as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood” (Hunt et al, 2005; Yancy et al, 2013)
While Sussan et al (2009) found that global KO of Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) enhances cigarette smoke–induced cardiac dysfunction in mice, we further demonstrated that the loss of Nrf2 function accelerates the transition from cardiac compensatory adaptation to heart failure in a setting of pressure overload (Li et al, 2009b)
As we demonstrated that pharmacological activation of Nrf2 suppresses oxidative stress-dependent death in cardiac myocytes (Ichikawa et al, 2009; Li et al, 2010), Zhang et al (2010) documented that Nrf2-deficient cardiomyocytes are more susceptible to 4-hydroxy-2-nonenal (4-HNE) challenge, and the cardiac protection of 4-HNE pre-conditioning is dependent on Nrf2-operated antioxidant defense
Summary
Heart failure is defined as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood” (Hunt et al, 2005; Yancy et al, 2013). We have established that pressure overload via TAC initially results in an adaptive cardiac hypertrophy with preserved cardiac function (weeks 1–2) followed by maladaptive cardiac remodeling and dysfunction (weeks 2–4), which eventually causes heart failure in wild-type mice (Li et al, 2009b) Using this TAC model, we found that TAC-induced myocardial necrosis and death rate are increased in Nrf KO mice in a C57BL/6J genetic background within first 2 weeks (Qin et al, 2016). Genetic inhibition of autophagy, such as CR-Atg KO, in combination with pharmacological kinase inhibitors, demonstrated that cardiac autophagy inhibition activates Fyn-operating Nrf nuclear export for degradation, enhancing Nrf2-driven transcription of angiotensinogen in cardiomyocytes, thereby leading to pathological activation of renin-angiotensin system in pressure overloaded hearts These results are seemly contradictory to our findings that Nrf activation enhances autophagosome formation and autophagic degradation of protein aggregates, thereby protecting against 4-week TAC-induced cardiac maladaptive remodeling and dysfunction in FVB/N mice (Wang et al, 2014). On the other hand, Erkens et al (2018) reported that global KO of Nrf attenuates myocardial ischemia-reperfusion injury and dysfunction most likely due to TABLE 1 | Nrf signaling cascade in mediating cardiac damage and dysfunction
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