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.
Highlights
Introduction published maps and institutional affilObesity is a public health problem worldwide with constant prevalence
The development of cardiovascular diseases (CVDs) is intimately linked to the pathogenesis of obesity, which includes an increase in the levels of circulating free fatty acid (FFA; including palmitate), reactive oxygen species (ROS) and reactive nitrogen species (RNS), causing chronic inflammation, which is another important source of oxidative stress, and insulin resistance [16,18]
Obesity-associated CVD developments are orchestrated by the dysregulation of adipokines and other adipose-derived signaling molecules due to adipose tissue dysfunction, increasing free fatty acids (FFAs) levels, and ROS and pro-inflammatory cytokines production, which are exacerbated by numerous pathological conditions associated with obesity, such as hyperglycemia, dyslipidemia, oxidative stress, endothelial dysfunction, hypertension, and atherosclerosis
Summary
NRF2 was first discovered in 1994 during research on β-globin gene regulation (reviewed in [22,23]). NRF2/ARE signaling is highly conserved in all species and regulates the expression of over 1000 genes in the cell under normal and stressed conditions, including cytoprotective and detoxifying phase II enzymes (reviewed in [20,22,23,25]). Cardiacspecific overexpression of Nfe2l2 (caNfe2l2) in mouse models have been used to induce pro-reductive and reductive stress, and these mice exhibited increased expression of genes such as glutamate-cysteine ligase catalytic subunit (Gclc), glutamate-cysteine ligase modifier subunit (Gclm), glutathione-disulfide reductase (Gsr) with previous name glutathione reductase, Nqo, GST Mu 1 (Gstm1), and Gpx, including the glutathione (Gsh), which is a key regulator of the cellular thiol redox state [38]. As recently reviewed by Zhou et al, another study showed that cardiomyocyte restricted transgenic overexpression of NRF2 protects against myocardial oxidative stress, cell death, fibrosis, hypertrophy, and dysfunction in mice with pressure overload induced by 4 weeks of transverse aortic arch constriction (reviewed in [4])
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