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

Vasanthi R. Muthusamy, Sankaranarayanan Kannan, Kamal Sadhaasivam, Sellamuthu S. Gounder, Christopher J. Davidson, Christoph Boeheme, John R. Hoidal, Li Wang, Namakkal Soorappan Rajasekaran

Research output: Contribution to journalArticlepeer-review

244 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)366-376
Number of pages11
JournalFree Radical Biology and Medicine
Volume52
Issue number2
DOIs
StatePublished - Jan 15 2012

Keywords

  • AES
  • Exercise
  • Keap1
  • Nrf2
  • Oxidative stress
  • ROS

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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