Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice

Jarrod A. Call, Jean Donet, Kyle S. Martin, Ashish K. Sharma, Xiaobin Chen, Jiuzhi Zhang, Jie Cai, Carolina A. Galarreta, Mitsuharu Okutsu, Zhongmin Du, Vitor A. Lira, Mei Zhang, Borna Mehrad, Brian H. Annex, Alexander L. Klibanov, Russell P. Bowler, Victor E. Laubach, Shayn M. Peirce, Zhen Yan

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Multiple organ dysfunction syndrome (MODS) is a detrimental clinical complication in critically ill patients with high mortality. Emerging evidence suggests that oxidative stress and endothelial activation (induced expression of adhesion molecules) of vital organ vasculatures are key, early steps in the pathogenesis. We aimed to ascertain the role and mechanism(s) of enhanced extracellular superoxide dismutase (EcSOD) expression in skeletal muscle in protection against MODS induced by endotoxemia. We showed that EcSOD overexpressed in skeletal muscle-specific transgenic mice (TG) redistributes to other peripheral organs through the circulation and enriches at the endothelium of the vasculatures. TG mice are resistant to endotoxemia (induced by lipopolysaccharide [LPS] injection) in developing MODS with significantly reduced mortality and organ damages compared with the wild type littermates (WT). Heterogenic parabiosis between TG and WT mice conferred a significant protection to WT mice, whereas mice with R213G knock-in mutation, a human single nucleotide polymorphism leading to reduced binding EcSOD in peripheral organs, exacerbated the organ damages. Mechanistically, EcSOD inhibits vascular cell adhesion molecule 1 expression and inflammatory leukocyte adhesion to the vascular wall of vital organs, blocking an early step of the pathology in organ damage under endotoxemia. Therefore, enhanced expression of EcSOD in skeletal muscle profoundly protects against MODS by inhibiting endothelial activation and inflammatory cell adhesion, which could be a promising therapy for MODS.

Original languageEnglish (US)
Pages (from-to)212-223
Number of pages12
JournalFree Radical Biology and Medicine
StatePublished - Dec 2017
Externally publishedYes


  • EcSOD
  • Endothelial activation
  • Endotoxemia
  • Free radicals
  • MODS
  • Oxidative stress
  • Parabiosis
  • Skeletal muscle
  • VCAM-1

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


Dive into the research topics of 'Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice'. Together they form a unique fingerprint.

Cite this