TY - JOUR
T1 - Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium
AU - Muthusamy, Vasanthi R.
AU - Kannan, Sankaranarayanan
AU - Sadhaasivam, Kamal
AU - Gounder, Sellamuthu S.
AU - Davidson, Christopher J.
AU - Boeheme, Christoph
AU - Hoidal, John R.
AU - Wang, Li
AU - Rajasekaran, Namakkal Soorappan
N1 - Funding Information:
This work is supported by the Center on Aging (CoA), Utah-Pilot Grant Program Award, Beginning Grant-In Aid from the AHA (086501F), and the University of Utah Interdisciplinary Seed Grant to Namakkal Soorappan Rajasekaran. Nrf2−/− mice, protocol, and primers for genotyping were kindly provided by Dr. Li Wang. We are grateful to Dr. Mark A. Supiano (Director of Center on Aging) for his support and valuable comments on this project. Thanks to Dr. John Michael, Dr. Robert Paine III and the Division of Cardiology for seed funding. We appreciate and thank Dr. Goutam Karan for his expert help in performing whole-heart images/microscopy. The authors thank Corey J. Miller for editorial assistance.
PY - 2012/1/15
Y1 - 2012/1/15
N2 - 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.
AB - 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.
KW - AES
KW - Exercise
KW - Keap1
KW - Nrf2
KW - Oxidative stress
KW - ROS
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U2 - 10.1016/j.freeradbiomed.2011.10.440
DO - 10.1016/j.freeradbiomed.2011.10.440
M3 - Article
C2 - 22051043
AN - SCOPUS:84855451533
SN - 0891-5849
VL - 52
SP - 366
EP - 376
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 2
ER -