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Publication
NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of
Soluble Epoxide Hydrolase.
Authors Stevenson MD, Canugovi C, Vendrov AE, Hayami T, Bowles DE, Krause KH, Madamanchi
NR, Runge MS
Submitted By Submitted Externally on 4/13/2020
Status Published
Journal Antioxidants & redox signaling
Year 2019
Date Published 7/1/2019
Volume : Pages 31 : 39 - 58
PubMed Reference 30450923
Abstract 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.




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