The Role of Nrf2-Mediated Pathway in Cardiac Remodeling and Heart Failure

Abstract

Heart failure (HF) is frequently the consequence of sustained, abnormal neurohormonal, and mechanical stress and remains a leading cause of death worldwide. The key pathophysiological process leading to HF is cardiac remodeling, a term referring to maladaptation to cardiac stress at the molecular, cellular, tissue, and organ levels. HF and many of the conditions that predispose one to HF are associated with oxidative stress. Increased generation of reactive oxygen species (ROS) in the heart can directly lead to increased necrosis and apoptosis of cardiomyocytes which subsequently induce cardiac remodeling and dysfunction. Nuclear factor-erythroid-2- (NF-E2-) related factor 2 (Nrf2) is a transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes that are ubiquitously expressed in the cardiovascular system. Emerging evidence has revealed that Nrf2 and its target genes are critical regulators of cardiovascular homeostasis via the suppression of oxidative stress, which is the key player in the development and progression of HF. The purpose of this review is to summarize evidence that activation of Nrf2 enhances endogenous antioxidant defenses and counteracts oxidative stress-associated cardiac remodeling and HF.

Oxidative stress biomarkers in pediatric sepsis: a prospective observational pilot study

“…Previously, a higher tissue SOD activity has been reported in an animal model of sepsis [18], and a higher plasmatic SOD activity was observed in adult patients with sepsis [19]. These results can be explained by a compensatory response to a pro-oxidant status by genetic transcription mechanisms induced by ROSmediated activation of nuclear factor Nrf2 (nuclear factor erythroid 2 -related factor 2) [20]. In contrast, because of a lack of the nucleus, it would not be possible to observe these compensatory mechanisms in erythrocytes.…”

The Effect of Nrf2 on Diabetic Complications

“…Oxidative stress destroys critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. If Nrf2 is not ubiquitinated, it builds up in the cytoplasm and is translocated into the nucleus [4][5][6].…”

“…DCM is related to oxidative stress that is due to imbalance between ROS and/or reactive nitrogen species generation and their clearance by antioxidant defense systems [2][3][4][5][6]. Experimental and clinical studies have shown the important roles that Nrf2 and its downstream genes play in the pathogenesis of cardiac remodeling and heart failure induced by a number of factors.…”

“…Experimental and clinical studies have shown the important roles that Nrf2 and its downstream genes play in the pathogenesis of cardiac remodeling and heart failure induced by a number of factors. TNF-α has an important role in a number of pathologies associated with oxidative stress including diabetes, cancer, cardiac hypertrophy, and cardiomyopathy [6,13].…”

“…Some antioxidants protect the heart from ischemia-induced cardiac injury via the Nrf2 pathway. For example, α-lipoic acid and prostaglandin D2 signiicantly increased Nrf2 nuclear translocation; the expression of its downstream genes reduced lactate dehydrogenase (LDH) and creatine kinase (CK) release, atenuated myocardial infarct size, decreased cardiomyocyte apoptosis, and partially preserved heart function; and this efect was at least partially PI3K/Akt signaling pathway dependent [6,14,15].…”