The Role of NRF2 in Obesity-Associated Cardiovascular Risk Factors

Abstract

The raising prevalence of obesity is associated with an increased risk for cardiovascular diseases (CVDs), particularly coronary artery disease (CAD), and heart failure, including atrial fibrillation, ventricular arrhythmias and sudden death. Obesity contributes directly to incident cardiovascular risk factors, including hyperglycemia or diabetes, dyslipidemia, and hypertension, which are involved in atherosclerosis, including structural and functional cardiac alterations, which lead to cardiac dysfunction. CVDs are the main cause of morbidity and mortality worldwide. In obesity, visceral and epicardial adipose tissue generate inflammatory cytokines and reactive oxygen species (ROS), which induce oxidative stress and contribute to the pathogenesis of CVDs. Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by Nfe2l2 gene) protects against oxidative stress and electrophilic stress. NRF2 participates in the regulation of cell inflammatory responses and lipid metabolism, including the expression of over 1000 genes in the cell under normal and stressed environments. NRF2 is downregulated in diabetes, hypertension, and inflammation. Nfe2l2 knockout mice develop structural and functional cardiac alterations, and NRF2 deficiency in macrophages increases atherosclerosis. Given the endothelial and cardiac protective effects of NRF2 in experimental models, its activation using pharmacological or natural products is a promising therapeutic approach for obesity and CVDs. This review provides a comprehensive summary of the current knowledge on the role of NRF2 in obesity-associated cardiovascular risk factors.

Protective Effects of Amauroderma rugosum on Doxorubicin-Induced Cardiotoxicity through Suppressing Oxidative Stress, Mitochondrial Dysfunction, Apoptosis, and Activating Akt/mTOR and Nrf2/HO-1 Signaling Pathways

“…Although oxidative stress is the most widely studied cause, accumulating evidence has indicated that a dysfunction in the nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase- (HO-) 1 pathway is also closely involved in the regulation of Dox-induced cardiotoxicity. Nrf2 is a transcription factor responsible for the regulation of cellular redox balance and protective antioxidant and phase II detoxification responses in mammals [ 8 ]. Under physiological conditions, Nrf2 combines with proteasomal degradation in the cytosol by the 26S proteasome via the cytoplasmic binding protein kelch-like epichlorohydrin-related protein (Keap) 1 [ 9 ].…”

NRF2 Mediates Cellular Resistance to Transformation, Radiation, and Inflammation in Mice

“…Keap1–/– mice die postnatally within 3 weeks as constitutive Nrf2 expression drives hyperkeratosis in the esophagus and forestomach [ 18 ]. While NRF2 is accepted as the master of oxidative/electrophilic stress responses, the literature points to roles for NRF2 in multiple biological processes [ 19 , 20 ]. Its clinical relevance in cancer biology and treatment is shown by NRF2 being dysregulated in many human cancers [ 21 , 22 , 23 , 24 , 25 ], especially where activating mutations, deletions, or gene amplifications affect NRF2/KEAP1 function to promote constitutive Nrf2 expression [ 15 , 26 ], with increased therapeutic resistance and poor outcomes [ 21 , 22 , 23 , 24 , 25 ].…”

Effect of sulfasalazine on endothelium-dependent vascular response by the activation of Nrf2 signalling pathway

“…Similarly, in a latest study conducted by Yao et al (2020) kaempferol protects blood vessels from damage in association with Nrf2/HO-1 signaling pathway. This assumption is supported by the finding that Nrf2 deficiency might accelerate the progression of type I and type II diabetes (Aleksunes et al, 2010;Bitar and Al-Mulla, 2011;Gutiérrez-Cuevas et al, 2022). In previous studies, it was reported that TAS copes with oxidative stress (Devasagayam et al, 2004;Strycharz-Dudziak et al, 2019).…”