Nrf2 as a Potential Mediator of Cardiovascular Risk in Metabolic Diseases

Abstract

Free radicals act as secondary messengers, modulating a number of important biological processes, including gene expression, ion mobilization in transport systems, protein interactions and enzymatic functions, cell growth, cell cycle, redox homeostasis, among others. In the cardiovascular system, the physiological generation of free radicals ensures the integrity and function of cardiomyocytes, endothelial cells, and adjacent smooth muscle cells. In physiological conditions, there is a balance between free radicals generation and the activity of enzymatic and non-enzymatic antioxidant systems. Redox imbalance, caused by increased free radical’s production and/or reduced antioxidant defense, plays an important role in the development of cardiovascular diseases, contributing to cardiac hypertrophy and heart failure, endothelial dysfunction, hypertrophy and hypercontractility of vascular smooth muscle. Excessive production of oxidizing agents in detriment of antioxidant defenses in the cardiovascular system has been described in obesity, diabetes mellitus, hypertension, and atherosclerosis. The transcription factor Nrf2 (nuclear factor erythroid 2–related factor 2), a major regulator of antioxidant and cellular protective genes, is primarily activated in response to oxidative stress. Under physiological conditions, Nrf2 is constitutively expressed in the cytoplasm of cells and is usually associated with Keap-1, a repressor protein. This association maintains low levels of free Nrf2. Stressors, such as free radicals, favor the translocation of Nrf2 to the cell nucleus. The accumulation of nuclear Nrf2 allows the binding of this protein to the antioxidant response element of genes that code antioxidant proteins. Although little information on the role of Nrf2 in the cardiovascular system is available, growing evidence indicates that decreased Nrf2 activity contributes to oxidative stress, favoring the pathophysiology of cardiovascular disorders found in obesity, diabetes mellitus, and atherosclerosis. The present mini-review will provide a comprehensive overview of the role of Nrf2 as a contributing factor to cardiovascular risk in metabolic diseases.

Dietary Cocoa Prevents Aortic Remodeling and Vascular Oxidative Stress in Diabetic Rats

“…Taken together, these outcomes indicate that cocoa diet avoids diabetes‐induced depletion of Nrf2 and their antioxidants enzymes, mainly MT, contributing to prevent oxidative stress and vascular injury in diabetic rats. Although the role of Nrf2 in diabetes is not fully understood, it has been indicated that decreased Nrf2 activity in arteries contributes to oxidative stress and favours vascular remodeling and dysfunction in diabetes . Accordingly, the increase of Nrf2 activity by several activators has been considered as a promising approach for preventing the development of vascular complications in diabetes.…”

The size‐dependent genotoxic potentials of titanium dioxide nanoparticles to endothelial cells

“…Also, the consequences of DNA damage, including growth arrest, cell senescence, and apoptosis, are all increased in plaque microenvironment and their levels are correlated with increased severity of atherosclerosis . Additionally, the Nrf2, which controls the expression of antioxidant response element‐dependent genes to regulate cellular resistance to oxidants, is an universal guardian against oxidative and electrophilic stresses induced by toxicants in human organs and/or tissues, especially for cardiovascular system, and a key marker for cellular oxidative stress . Intriguingly, altered expression of Nrf2 is also associated with atherosclerosis .…”

“…[25][26][27] Additionally, the Nrf2, which controls the expression of antioxidant response element-dependent genes to regulate cellular resistance to oxidants, is an universal guardian against oxidative and electrophilic stresses induced by toxicants in human organs and/or tissues, especially for cardiovascular system, and a key marker for cellular oxidative stress. 45,46 Intriguingly, altered expression of Nrf2 is also associated with atherosclerosis. 55 In the present study, the results showed that these TiO 2 -NPs could elicit a significant increase of DNA damage and MN frequency in HUVECs in culture (Figures 1 and 2).…”

“…The intracellular redox statuses of HUVECs exposed to these NPs were also explored through the measurement of the levels of reactive oxygen species (ROS) production and reduced glutathione (GSH), respectively. The protein levels of nuclear factor erythroid 2‐related factor 2 (Nrf2), a key protein in the antioxidant defense system of mammalian cells and a critical marker for cellular oxidative stress, were also detected by western blot. We mainly focused on the size‐dependent oxidative‐genotoxicity of TiO 2 ‐NP exposure on HUVECs in culture.…”

“…The protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), a key protein in the antioxidant defense system of mammalian cells and a critical marker for cellular oxidative stress, 45,46 were also detected by western blot. We mainly focused on the size-dependent oxidative-genotoxicity of TiO 2 -NP exposure on HUVECs in culture.…”