Enhanced Keap1-Nrf2 signaling protects the myocardium from isoproterenol-induced pathological remodeling in mice

Gobinath Shanmugam; Anil Kumar Challa; Silvio H. Litovsky; Asokan Devarajan; Ding Wang; Dean P. Jones; Victor M. Darley-Usmar; Namakkal Soorappan Rajasekaran

Redox Biology (Oct 2019)

Enhanced Keap1-Nrf2 signaling protects the myocardium from isoproterenol-induced pathological remodeling in mice

Gobinath Shanmugam,
Anil Kumar Challa,
Silvio H. Litovsky,
Asokan Devarajan,
Ding Wang,
Dean P. Jones,
Victor M. Darley-Usmar,
Namakkal Soorappan Rajasekaran

Affiliations

Gobinath Shanmugam: Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
Anil Kumar Challa: Department of Biology, University of Alabama at Birmingham, Birmingham, AL, USA
Silvio H. Litovsky: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
Asokan Devarajan: Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
Ding Wang: NIH BD2K Center of Excellence for Biomedical Computing at UCLA and Department of Physiology, University of California, Los Angeles, USA
Dean P. Jones: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
Victor M. Darley-Usmar: Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
Namakkal Soorappan Rajasekaran: Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; Corresponding author. Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, UAB|The University of Alabama at Birmingham, BMR2 Room 533|901 19th Street South, Birmingham, AL 35294-2180, USA.

Journal volume & issue: Vol. 27

Abstract

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Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/Nrf2) is an inducible transcription factor that is essential for maintenance of redox signaling in response to stress. This suggests that if Nrf2 expression response could be enhanced for a defined physiological pro-oxidant stress then it would be protective. This has important implications for the therapeutic manipulation of the Keap1/Nrf2 signaling pathway which is now gaining a lot of attention. We tested this hypothesis through the generation of Nrf2 transgene expression mouse model with and without isoproterenol-induced cardiac stress. Cardiac-specific mouse Nrf2 transgenic (mNrf2-TG) and non-transgenic (NTG) mice were subjected to isoproterenol (ISO) treatment and assessed for myocardial structure, function (echocardiography and electrocardiography), and glutathione redox state. Myocardial infarction and fibrosis along with increased inflammation leading to myocardial dysfunction was noted in NTG mice exposed to ISO, while mNrf2-TG hearts were resistant to the ISO insult. Preservation of myocardial structure and function in the mNrf2-TG mice was associated with the enhanced Nrf2 expression displayed in these hearts with an increased basal and post-treatment expression of redox modulatory genes and an overall enhanced antioxidant status. Of note, myocardium of ISO-treated TG mice displayed significantly increased stabilization of the KEAP1-NRF2 complex and enhanced release of NRF2 to the nucleus resulting in overall decreased pro-oxidant markers. Taken together, we suggest that a basal enhanced Nrf2 expression in mouse heart results in maintenance of redox homeostasis and counteracts ISO-induced oxidative stress, and suppresses pathological remodeling. These data suggest that an alternative therapeutic approach to enhance the efficacy of the Keap1-Nrf2 system is to stimulate basal expression of Nrf2. Keywords: Nrf2, Isoproterenol, Antioxidants, Cardiac remodeling, Echocardiography

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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