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NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of Soluble Epoxide Hydrolase.

Publication ,  Journal Article
Stevenson, MD; Canugovi, C; Vendrov, AE; Hayami, T; Bowles, DE; Krause, K-H; Madamanchi, NR; Runge, MS
Published in: Antioxid Redox Signal
July 1, 2019

Aims: Oxidative stress is implicated in cardiomyocyte cell death and cardiac remodeling in the failing heart. The role of NADPH oxidase 4 (NOX4) in cardiac adaptation to pressure overload is controversial, but its function in myocardial ischemic stress has not been thoroughly elucidated. This study examined the function of NOX4 in the pathogenesis of ischemic heart failure, utilizing mouse models, cell culture, and human heart samples. Results:Nox4-/- mice showed a protective phenotype in response to permanent left anterior descending coronary artery ligation with smaller infarction area, lower cardiomyocyte cross-sectional area, higher capillary density, and less cell death versus wild-type (WT) mice. Nox4-/- mice had lower activity of soluble epoxide hydrolase (sEH), a potent regulator of inflammation. Nox4-/- mice also showed a 50% reduction in the number of infiltrating CD68+ macrophages in the peri-infarct zone versus WT mice. Adenoviral overexpression of NOX4 in cardiomyoblast cells increased sEH expression and activity and CCL4 and CCL5 levels; inhibition of sEH activity in NOX4 overexpressing cells attenuated the cytokine levels. Human hearts with ischemic cardiomyopathy showed adverse cardiac remodeling, increased NOX4 and sEH protein expression and CCL4 and CCL5 levels compared with control nonfailing hearts. Innovation and Conclusion: These data from the Nox4-/- mouse model and human heart tissues show for the first time that oxidative stress from increased NOX4 expression has a functional role in ischemic heart failure. One mechanism by which NOX4 contributes to ischemic heart failure is by increasing inflammatory cytokine production via enhanced sEH activity.

Duke Scholars

Published In

Antioxid Redox Signal

DOI

EISSN

1557-7716

Publication Date

July 1, 2019

Volume

31

Issue

1

Start / End Page

39 / 58

Location

United States

Related Subject Headings

  • Up-Regulation
  • Rats
  • NADPH Oxidase 4
  • Myocardial Ischemia
  • Mice
  • Humans
  • Heart Failure
  • Gene Knockout Techniques
  • Epoxide Hydrolases
  • Disease Models, Animal
 

Citation

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MLA
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Stevenson, M. D., Canugovi, C., Vendrov, A. E., Hayami, T., Bowles, D. E., Krause, K.-H., … Runge, M. S. (2019). NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of Soluble Epoxide Hydrolase. Antioxid Redox Signal, 31(1), 39–58. https://doi.org/10.1089/ars.2018.7548
Stevenson, Mark D., Chandrika Canugovi, Aleksandr E. Vendrov, Takayuki Hayami, Dawn E. Bowles, Karl-Heinz Krause, Nageswara R. Madamanchi, and Marschall S. Runge. “NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of Soluble Epoxide Hydrolase.Antioxid Redox Signal 31, no. 1 (July 1, 2019): 39–58. https://doi.org/10.1089/ars.2018.7548.
Stevenson MD, Canugovi C, Vendrov AE, Hayami T, Bowles DE, Krause K-H, et al. NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of Soluble Epoxide Hydrolase. Antioxid Redox Signal. 2019 Jul 1;31(1):39–58.
Stevenson, Mark D., et al. “NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of Soluble Epoxide Hydrolase.Antioxid Redox Signal, vol. 31, no. 1, July 2019, pp. 39–58. Pubmed, doi:10.1089/ars.2018.7548.
Stevenson MD, Canugovi C, Vendrov AE, Hayami T, Bowles DE, Krause K-H, Madamanchi NR, Runge MS. NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of Soluble Epoxide Hydrolase. Antioxid Redox Signal. 2019 Jul 1;31(1):39–58.
Journal cover image

Published In

Antioxid Redox Signal

DOI

EISSN

1557-7716

Publication Date

July 1, 2019

Volume

31

Issue

1

Start / End Page

39 / 58

Location

United States

Related Subject Headings

  • Up-Regulation
  • Rats
  • NADPH Oxidase 4
  • Myocardial Ischemia
  • Mice
  • Humans
  • Heart Failure
  • Gene Knockout Techniques
  • Epoxide Hydrolases
  • Disease Models, Animal