NADPH Oxidases in Heart Failure: Poachers or Gamekeepers?

Min Zhang, Alessia Perino, Alessandra Ghigo, Emilio Hirsch, Ajay M. Shah*

*Corresponding author for this work

Research output: Contribution to journalLiterature reviewpeer-review

169 Citations (Scopus)

Abstract

Significance: Oxidative stress is involved in the pathogenesis of heart failure but clinical antioxidant trials have been unsuccessful. This may be because effects of reactive oxygen species (ROS) depend upon their source, location, and concentration. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) proteins generate ROS in a highly regulated fashion and modulate several components of the heart failure phenotype. Recent Advances: Two Nox isoforms, Nox2 and Nox4, are expressed in the heart. Studies using gene-modified mice deficient in Nox2 activity indicate that Nox2 activation contributes to angiotensin II-induced cardiomyocyte hypertrophy, atrial fibrillation, and the development of interstitial fibrosis but may also positively modulate physiological excitation-contraction coupling. Nox2 contributes to myocyte death under stress situations and plays important roles in postmyocardial infarction remodeling, in part by modulating matrix metalloprotease activity. In contrast to Nox2, Nox4 is constitutively active at a low level and induces protective effects in the heart under chronic stress, for example, by maintaining myocardial capillary density. However, high levels of Nox4 could have detrimental effects. Critical Issues: The effects of Nox proteins during the development of heart failure likely depend upon the isoform, activation level, and cellular distribution, and may include beneficial as well as detrimental effects. More needs to be learnt about the precise regulation of abundance and biochemical activity of these proteins in the heart as well as the downstream signaling pathways that they regulate. Future Directions: The development of specific approaches to target individual Nox isoforms and/or specific cell types may be important for the achievement of therapeutic efficacy in heart failure. 

Original languageEnglish
Article numberN/A
Pages (from-to)1024-1041
Number of pages18
JournalANTIOXIDANTS AND REDOX SIGNALING
Volume18
Issue number9
DOIs
Publication statusPublished - 20 Mar 2013

Keywords

  • VASCULAR SMOOTH-MUSCLE
  • INDUCED CARDIAC DYSFUNCTION
  • EXPERIMENTAL MYOCARDIAL-INFARCTION
  • INDUCED CARDIOMYOCYTE HYPERTROPHY
  • CHRONIC GRANULOMATOUS-DISEASE
  • DEHYDROGENASE-DERIVED NADPH
  • SIGNAL-REGULATING KINASE-1
  • NUCLEOTIDE EXCHANGE FACTOR
  • OXIDE SYNTHASE ACTIVATION
  • RESPIRATORY BURST OXIDASE

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