Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury.

Qiujun Yu, Chi Fung Lee, Wang Wang, Georgios Karamanlidis, Junya Kuroda, Shouji Matsushima, Junichi Sadoshima, Rong Tian

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The NADPH oxidase family (Nox) produces reactive oxygen species by adding the electron donated by NADPH to oxygen. Excessive reactive oxygen species production under a variety of pathological conditions has been attributed to increased Nox activity. Here, we aimed at investigating the role of Nox in cardiac ischemic injury through gain- and loss-of-function approaches. We modulated Nox activity in the heart by cardiac-specific expression of Nox4 and dominant negative Nox4. Modulation of Nox activity drastically changes the cellular redox status. Increasing Nox activity by cardiac-specific overexpression of Nox4 imposed oxidative stress on the myocardium [increased NAD(P)(+)/NAD(P)H and decreased glutathione/glutathione disulfide ratio] and worsened cardiac energetics and contractile function after ischemia-reperfusion. Overexpression of the dominant negative Nox4 (DN), which abolished the Nox function, led to a markedly reduced state [decreased NAD(P)(+)/NAD(P)H and increased glutathione/glutathione disulfide ratio] at baseline and paradoxically promoted mitochondrial reactive oxygen species production during ischemia resulting in no recovery of heart function after reperfusion. Limiting the generation of reducing equivalent through modulating carbon substrates availability partially restored the NAD(+)/NADH ratio and protected dominant negative Nox4 hearts from ischemic injury. This study reveals an important role of Nox in cardiac redox regulation and highlights the complexity of developing therapies that affect the intricately connected redox states.

Original languageEnglish
Pages (from-to)e000555
JournalJournal of the American Heart Association
Volume3
Issue number1
DOIs
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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