Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway

Redox Biol. 2018 May;15:405-417. doi: 10.1016/j.redox.2017.12.016. Epub 2018 Jan 2.

Abstract

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)-3β, 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-3β-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-3β/Fyn-mediated Nrf2 activation.

Keywords: Angiotensin II; Cardiomyopathy; Nrf2 activator; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism
  • Animals
  • Diabetic Cardiomyopathies / drug therapy*
  • Diabetic Cardiomyopathies / genetics
  • Diabetic Cardiomyopathies / metabolism
  • Diabetic Cardiomyopathies / pathology
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 beta / genetics*
  • Heart / drug effects
  • Heart / physiopathology
  • Humans
  • Isothiocyanates / administration & dosage*
  • Male
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics*
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-fyn / genetics*
  • Signal Transduction / drug effects
  • Sulfoxides

Substances

  • Isothiocyanates
  • NF-E2-Related Factor 2
  • Sulfoxides
  • Angiotensin II
  • Fyn protein, mouse
  • Proto-Oncogene Proteins c-fyn
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • sulforaphane