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.
Highlights
Edited by: Javier Egea, Institute of Health Research of the University Hospital of La Princesa, Spain
Little information on the role of nuclear factor erythroid 2-related factor-2 (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
Activation of the Nrf2-dependent antioxidant system plays an important role in cell defense against oxidative stress damage, whereas the insufficiency of the Nrf2 system is associated with multiple aspects of the genesis and progression of metabolic diseases, posing a great risk to the cardiovascular system (Figure 1)
Summary
Reactive oxygen species (ROS) were initially presumed to cause cell damage, they are recognized as important molecules that regulate many cell signaling and biological processes, such as induction of defense genes, activation of transcription factors, phosphorylation of kinases, and mobilization of ions in transport systems (reviewed in Droge, 2002; Touyz and Briones, 2011; Brown and Griendling, 2015). When compared to wild-type mice, the white adipose tissue of obese mice expresses substantially higher levels of many genes related to antioxidant response, inflammation, adipogenesis, lipogenesis, glucose uptake, and lipid transport (Xue et al, 2013) These findings support a role for Nrf in regulating adipose tissue development and function, insulin sensitivity, glucose and lipid homeostasis. The apparent contradictory role of Nrf protecting mice from obesity and insulin resistance in conditions of Nrf deficiency in comparison to Nrf pharmacological activation, may be explained by the observations that Nrf deficiency leads to a mild increase in the levels of ROS, which stimulate the antioxidant system in a manner similar to the Nrf activators (reviewed in Bocci et al, 2014) Another possible explanation is that Nrf activators regulate non-Nrf signaling pathways to modulate glucose and lipid metabolism. Endothelial dysfunction in diabetes is associated with enhanced vascular contractility, oxidative stress and vascular inflammation
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