SOD3 variant, R213G, altered SOD3 function, leading to ROS-mediated inflammation and damage in multiple organs of premature aging mice

Myung Ja Kwon, Kyo Young Lee, Han Woong Lee, Jung Ho Kim, Tae Yoon Kim

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Aims: Among the isoforms of superoxide dismutase, SOD3 is uniquely associated with the extracellular matrix (ECM) by virtue of its heparin-binding domain (HBD). Substitution of arginine by glycine at amino acid 213 (R213G) of its HBD was first identified in patients with heart failure, followed by many studies that focused on the role of this variant (SOD3R213G) in ischemic heart disease and cardiovascular disease. However, the biological significance of this mutation in a physiological context is largely unknown. Results: As a first step, we generated SOD3R213G transgenic mice, in which the variant gene was driven by the β-actin promoter allowing expression in all tissues. Unexpectedly, we found that SOD3R213G transgenic mice exhibited premature aging, including hair graying, abnormal gait, and a shortened life span. Specifically, the aged mice showed systemic inflammation and organ degeneration. In addition, aged SOD3R213G mice are susceptible to neutrophil-mediated inflammation. Among other functions, the neutrophils of SOD3R213G mice produce high amounts of reactive oxygen species, which would normally be controlled by SOD3 in ECM. Innovation: These findings showed for the first time that arginine 213 in the HBD of SOD3 is critical for maintaining proper organ function through moderating the normal innate immune response, which would otherwise lead to chronic inflammation and degenerative diseases in aged mice. Conclusion: Therefore, patients with this variant may be treated with SOD3 as a therapeutic strategy to prevent or cure these diseases.

Original languageEnglish
Pages (from-to)985-999
Number of pages15
JournalAntioxidants and Redox Signaling
Volume23
Issue number12
DOIs
Publication statusPublished - 2015 Oct 20

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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