Current Status and Challenges of NRF2 as a Potential Therapeutic Target for Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy is one of the main causes of heart failure and death in patients with diabetes mellitus. Reactive oxygen species produced excessively in diabetes mellitus cause necrosis, apoptosis, ferroptosis, inflammation, and fibrosis of the myocardium as well as impair the cardiac structure and function. It is increasingly clear that oxidative stress is a principal cause of diabetic cardiomyopathy. The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2) activates the transcription of more than 200 genes in the human genome. Most of the proteins translated from these genes possess anti-oxidant, anti-inflammatory, antiapoptotic, anti-ferroptotic, and anti-fibrotic actions. There is a growing body of evidence indicating that NRF2 and its target genes are crucial in preventing high glucose-induced oxidative damage in diabetic cardiomyopathy. Recently, many natural and synthetic activators of NRF2 are shown to possess promising therapeutic effects on diabetic cardiomyopathy in animal models of diabetic cardiomyopathy. Targeting NRF2 signaling by pharmacological entities is a potential approach to ameliorating diabetic cardiomyopathy. However, the persistent high expression of NRF2 in cancer tissues also protects the growth of cancer cells. This "dark side" of NRF2 increases the challenges of using NRF2 activators to treat diabetic cardiomyopathy. In addition, some NRF2 activators were found to have off-target effects. In this review, we summarize the current status and challenges of NRF2 as a potential therapeutic target for diabetic cardiomyopathy.

Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat

“…Downregulation of CMKLR1 suppressed cardiac cell death in DCM rats. Although apoptosis and necrosis are the forms of cell death that are normally detected in DCM patients (Chowdhry et al, 2007;D'Arcy, 2019;Ge et al, 2019;Qi et al, 2020) recent studie have shown that other types of cell death, such as pyroptosis, are also found in DCM (Wang X. et al, 2019). Pyroptosis is a type of programmed cell death that is commonly induced by caspase-1 activation, and is characterized by pore formation on the plasma membrane, cell swelling, nuclear DNA damage, and release of intracellular inflammatory content (Liu et al, 2016;Lacey et al, 2018).…”

Allopurinol reduces oxidative stress and activates Nrf2/p62 to attenuate diabetic cardiomyopathy in rats

“…8,9 We recently showed that cardiac Nrf2 was reduced in streptozotocin (STZ)-induced diabetic rats and strategies that enhanced cardiac Nrf2 could activate myocardial HO-1 and attenuate cardiac hypertrophy and cardiac dysfunction in diabetic rats. 11,12 However, the potential impact of allopurinol (ALP) on cardiac Nrf2 expression in diabetes and its underlying mechanism of action have not been explored. 11,12 However, the potential impact of allopurinol (ALP) on cardiac Nrf2 expression in diabetes and its underlying mechanism of action have not been explored.…”

“…10 Also, recent studies suggest that targeting Nrf2 may represent a mechanism by which treatments that can attenuate DCM. 11,12 However, the potential impact of allopurinol (ALP) on cardiac Nrf2 expression in diabetes and its underlying mechanism of action have not been explored.…”

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

“…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.…”