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

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.