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.

Figure 1

Roles of oxidative stress in cardiac remodeling and the potential protection by Nrf2 from oxidative damage. Hypertension, ischemia, diabetes, and anticancer drugs all induce additional generation of reactive oxygen and/or nitrogen species (ROS and/or RNS), leading to oxidative stress. Oxidative stress accelerates inflammation and apoptosis, which in turn causes cardiomyocyte hypertrophy and/or fibroblast proliferation, resulting in the cardiac remodeling (fibrosis). Meanwhile, ROS and/or RNS interact with cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. At the early stage of these pathological conditions, the released Nrf2 from Keap1 translocates to nucleus and combines with Maf and ARE to initiate the transcription of a number of antioxidative genes, such as SOD, CAT, and GPx, which are performing a wide range of cell defense processes against this pathological oxidative stress in the heart; however, at the late stage, Nrf2 may be exhausted or downregulated by its abnormal Nrf2 gene expression, leading to the failure to maintain the redox homeostasis by increasing ARE-mediated expression of phase II and antioxidant enzymes. Consequently, the persistently oxidative stress induces cardiac remodeling and finally heart failure.

Figure 2

Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. (a) The left panel shows representative pictures of hearts of wild-type (WT) and Nrf2^−/− mice after TAC. The right panel shows the heart weight/body weight (HW/BW) ratio. (b) Left ventricle fractional shortening (FS) (%) of WT and Nrf2^−/− mice 2 weeks after TAC. (c) Representative confocal microscopic images of LV 4-HNE staining. 4-HNE-positive staining is shown in red. Nuclei are shown in blue (×630). Nrf2 gain- and loss-of-function on hypertrophic factor-induced ROS production in rat neonatal cardiomyocytes. Representative images and quantitative analysis of intracellular ROS production in norepinephrine (NE, 200 μmol/L) or phenylephrine (PE, 100 μmol/L) treated cardiac myocytes that were infected with adenovirus of Nrf2 (d) or rat Nrf2 shRNA (e). *P < 0.05 or ^# P < 0.05 versus control ad-βGal- or ad-Nrf2-infected cells that were treated with vehicles. The combined figures here were collected by the authors from different figures published in the study by Li et al. [7].