Abstract
Oxidative stress is an important risk factor contributing to the pathogenesis of cardiovascular diseases. Oxidative stress that results from excessive reactive oxygen species (ROS) production accounts for impaired endothelial function, a process which promotes atherosclerotic lesion or fatty streaks formation (foam cells). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in cellular redox homeostasis. Upon exposure to oxidative stress, Nrf2 is dissociated from its inhibitor Keap-1 and translocated into the nucleus, where it results in the transcriptional activation of cell defense genes. Nrf2 has been demonstrated to be involved in the protection against foam cells formation by regulating the expression of antioxidant proteins (HO-1, Prxs, and GPx1), ATP-binding cassette (ABC) efflux transporters (ABCA1 and ABCG1) and scavenger receptors (scavenger receptor class B (CD36), scavenger receptor class A (SR-A) and lectin-type oxidized LDL receptor (LOX-1)). However, Nrf2 has also been reported to exhibit pro-atherogenic effects. A better understanding on the mechanism of Nrf2 in oxidative stress-induced cardiac injury, as well as the regulation of cholesterol uptake and efflux, are required before it can serve as a novel therapeutic target for cardiovascular diseases prevention and treatment.
Highlights
Cardiovascular diseases (CVD) including coronary heart disease (CHD), myocardial infarction (MI), and stroke are the leading causes of death globally, accounting for 31% of all global deaths (17.7 million) in 2015 [1]
Immune cells such as macrophages and dendritic cells are most often found in the intimal atherosclerotic lesions where they contribute to the inflammatory microenvironment of the lesions
This study suggests the importance of Nuclear factor erythroid 2-related factor 2 (Nrf2) in protecting against foam cells formation via regulation of receptors responsible for lipoprotein internalization in macrophages
Summary
Cardiovascular diseases (CVD) including coronary heart disease (CHD), myocardial infarction (MI), and stroke are the leading causes of death globally, accounting for 31% of all global deaths (17.7 million) in 2015 [1]. Nrf belongs to the cap “n” collar family of basic region-leucine zipper (CNC-bZIP) transcription factors that modulate the cellular redox status [14] It regulates genes which contain antioxidant/electrophile response elements (ARE/EpRE), including antioxidant and phase II detoxification enzymes, ABC transporters and other stress response protein expression. Exposure of cells to ROS, xenobiotics, heavy metals, oxLDL, electrophiles and pro-inflammatory cytokines, omega-3 polyunsaturated fatty acids (ω-3PUFA) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) [21,22,23] and natural dietary components with antioxidant properties including curcumin (turmeric), resveratrol and pterostilbene (grapes, blueberries), garlic (allicin), sulforaphane (broccoli, cruciferous) and green tea extract [22,24] results in the conformational change in Keap through modification of its cysteine residues These modifications disrupt the low-affinity interaction between the Keap Kelch domain and Nrf DLG-motif, which results in stabilization of Nrf. N-terminal kinase; NQO1, NADPH quinine oxidoreductase 1; GSTs, glutathione S-transferases; AKRs, aldo-keto reductases; GPX, glutathione peroxidase; GCLC, glutamate-cysteine ligase; GCLM, glutamate-cysteine ligase modifier subunit; GR, glutathione reductase; SOD, superoxide dismutase; TXN1, thioredoxin; TXNR, thioredoxin reductase 1, PRDX1, peroxiredoxin 1; HMOX1, heme oxygenase (decycling) 1; FECH, ferrochelatase, and; MRP, multidrug resistance-associated proteins
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