Nox1 NADPH oxidase is necessary for late but not early myocardial ischaemic preconditioning

Shuxia Jiang, Jennifer Streeter, Brandon M. Schickling, Kathy Zimmerman, Robert M. Weiss, Francis J. Miller

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

AimsIschaemic preconditioning (IPC) is an adaptive mechanism that renders the myocardium resistant to injury from subsequent hypoxia. Although reactive oxygen species (ROS) contribute to both the early and late phases of IPC, their enzymatic source and associated signalling events have not yet been understood completely. Our objective was to investigate the role of the Nox1 NADPH oxidase in cardioprotection provided by IPC.Methods and resultsWild-type (WT) and Nox1-deficient mice were treated with three cycles of brief coronary occlusion and reperfusion, followed by prolonged occlusion either immediately (early IPC) or after 24 h (late IPC). Nox1 deficiency had no impact on the cardioprotection afforded by early IPC. In contrast, deficiency of Nox1 during late IPC resulted in a larger infarct size, cardiac remodelling, and increased myocardial apoptosis compared with WT hearts. Furthermore, expression of Nox1 in WT hearts increased in response to late IPC. Deficiency of Nox1 abrogated late IPC-mediated activation of cardiac nuclear factor-κB (NF-κB) and induction of tumour necrosis factor-α (TNF-α) in the heart and circulation. Finally, knockdown of Nox1 in cultured cardiomyocytes prevented TNF-α induction of NF-κB and the protective effect of IPC on hypoxia-induced apoptosis.ConclusionsOur data identify a critical role for Nox1 in late IPC and define a previously unrecognized link between TNF-α and NF-κB in mediating tolerance to myocardial injury. These findings have clinical significance considering the emergence of Nox1 inhibitors for the treatment of cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)79-87
Number of pages9
JournalCardiovascular Research
Volume102
Issue number1
DOIs
StatePublished - Apr 2014

Bibliographical note

Funding Information:
This work was supported by the Office of Research and Development, Department of Veterans Affairs (1BX001729 to F.J.M.); the National Institutes of Health (HL081750 to F.J.M. and RR026293 to R.M.W.); and the American Heart Association (POST7640011 to S.J. and PRE12060526 to J.S.).

Keywords

  • Ischaemic preconditioning
  • Myocardial infarction
  • NF-κB
  • Nox1
  • TNF-α

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