Journal
REDOX BIOLOGY
Volume 15, Issue -, Pages 405-417Publisher
ELSEVIER
DOI: 10.1016/j.redox.2017.12.016
Keywords
Cardiomyopathy; Angiotensin II; Nrf2 activator; Oxidative stress
Categories
Funding
- National Natural Science Foundation of China [81570344, 81300186, 81470061, 81671378, 81273509, 81400281, 81370318, 81470495]
- Norman Bethune Program of Jilin University [2015225, 2015203]
- Jilin Provincial Science & Technology Foundations [20150204079SF, 20150204093SF, 20140519012JH]
- American Diabetes Association [1-15-BS-018]
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Aims: Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by sulforaphane (SFN) protects from, and deletion of the Nrf2 gene exaggerates, diabetic cardiomyopathy. Angiotensin II (Ang II) plays a critical role in the development of diabetic cardiomyopathy. Therefore, whether SFN prevents Ang II-induced cardiomyopathy through activation of Nrf2 was examined using wild-type, global deletion of Nrf2 gene (Nrf2-KO) and cardiomyocyte-specific overexpression of Nrf2 gene (Nrf2-TG) mice. Methods and results: Administration of a subpressor dose of Ang II to wild-type mice induced cardiac oxidative stress, inflammation, remodeling and dysfunction, all of which could be prevented by SFN treatment with Nrf2 up-regulation and activation. Nrf2-KO mice are susceptible, and Nrf2-TG mice are resistant, respectively, to Ang II-induced cardiomyopathy. Meanwhile, the ability of SFN to protect against Ang II-induced cardiac damage was lost in Nrf2-KO mice. Up-regulation and activation of Nrf2 by SFN is accompanied by activation of Akt, inhibition of glycogen synthase kinase (GSK)-3P, and accumulation of Fyn in nuclei. In vitro up-regulation of Nrf2 by SFN was abolished and nuclear Fyn accumulation was increased when cardiac cells were exposed to a PI3K inhibitor or GSK-3 beta-specific activator. Conclusion: These results suggest that Nrf2 plays a central role in the prevention of Ang II-induced cardiomyopathy, and SFN prevents Ang II-induced cardiomyopathy partially via the Akt/GSK-3 beta/Fyn-mediated Nrf2 activation.
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