Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium

• Published in: Free radical biology & medicine 2012-01, Vol.52 (2), p.366-376
• Main Authors: Muthusamy, Vasanthi R., Kannan, Sankaranarayanan, Sadhaasivam, Kamal, Gounder, Sellamuthu S., Davidson, Christopher J., Boeheme, Christoph, Hoidal, John R., Wang, Li, Rajasekaran, Namakkal Soorappan
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; AES; Animals; antioxidants; Antioxidants - metabolism; cardiovascular diseases; Cell Nucleus - metabolism; Cytoskeletal Proteins - metabolism; defense mechanisms; Exercise; Female; Gene Knockout Techniques; genes; Glutathione - metabolism; Heart - anatomy & histology; Heart - physiology; hypertrophy; infarction; Keap1; Kelch-Like ECH-Associated Protein 1; leucine zipper; Male; Mice; Mice, Knockout; myocardium; Myocardium - metabolism; NADPH Oxidase 4; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative Stress; pathogenesis; Physical Exertion; Protein Binding; Protein Transport; Reactive Oxygen Species - metabolism; Response Elements; ROS; Signal Transduction; stress response; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; transcription (genetics); Transcriptional Activation; Up-Regulation
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2011.10.440

Oxidative stress has been implicated in the pathogenesis of cardiovascular diseases, including myocardial hypertrophy and infarction. Although impairment of antioxidant defense mechanisms has been thought to provoke oxidative stress-induced myocardial dysfunction, it has been difficult to clearly demonstrate. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive, basic leucine zipper protein that regulates the transcription of several antioxidant genes. We previously reported that sustained activation of Nrf2 upregulates transcription of a number of endogenous antioxidants in the heart. Here, we show that acute exercise stress (AES) results in activation of Nrf2/ARE (antioxidant response element) signaling and subsequent enhancement of antioxidant defense pathways in wild-type (WT) mouse hearts, while oxidative stress, along with blunted defense mechanisms, was observed in Nrf2−/− mice. We also find that AES is associated with increased trans-activation of ARE-containing genes in exercised animals when compared to age-matched sedentary WT mice. However, enhanced oxidative stress in response to AES was observed in Nrf2−/− mice due to lower basal expression and marked attenuation of the transcriptional induction of several antioxidant genes. Thus, AES induces ROS and promotes Nrf2 function, but disruption of Nrf2 increases susceptibility of the myocardium to oxidative stress. Our findings suggest the basis for a nonpharmacological approach to activate Nrf2/ARE signaling, which might be a potential therapeutic target to protect the heart from oxidative stress-induced cardiovascular complications. [Display omitted] ► Under basal conditions, Nrf2 has a minimal role on antioxidant regulation in heart. ► Acute exercise stress triggers ROS and promotes Nrf2 nuclear translocation/ function. ► Increased Nrf2 activity up-regulates transcription of ARE-dependent antioxidants. ► Acute exercise represents a non-pharmacological inducer of Nrf2/ARE signaling. ► Abrogation of Nrf2 induces oxidative stress and impairs myocardial antioxidants.