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 journalArticle

Abstract

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
Volume113
DOIs
StatePublished - Dec 2017

Fingerprint

Multiple Organ Failure
Superoxide Dismutase
Muscle
Chemical activation
Endotoxemia
Muscles
Transgenic Mice
Skeletal Muscle
Adhesion
Parabiosis
Oxidative stress
Vascular Cell Adhesion Molecule-1
Mortality
Cell adhesion
Pathology
Polymorphism
Critical Illness
Cell Adhesion
Endothelium
Single Nucleotide Polymorphism

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice. / Call, Jarrod A.; Donet, Jean; Martin, Kyle S.; Sharma, Ashish K.; Chen, Xiaobin; Zhang, Jiuzhi; Cai, Jie; Galarreta, Carolina A.; Okutsu, Mitsuharu; Du, Zhongmin; Lira, Vitor A.; Zhang, Mei; Mehrad, Borna; Annex, Brian H.; Klibanov, Alexander L.; Bowler, Russell P.; Laubach, Victor E.; Peirce, Shayn M.; Yan, Zhen.

In: Free Radical Biology and Medicine, Vol. 113, 12.2017, p. 212-223.

Research output: Contribution to journalArticle

Call, JA, Donet, J, Martin, KS, Sharma, AK, Chen, X, Zhang, J, Cai, J, Galarreta, CA, Okutsu, M, Du, Z, Lira, VA, Zhang, M, Mehrad, B, Annex, BH, Klibanov, AL, Bowler, RP, Laubach, VE, Peirce, SM & Yan, Z 2017, 'Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice', Free Radical Biology and Medicine, vol. 113, pp. 212-223. https://doi.org/10.1016/j.freeradbiomed.2017.09.029
Call, Jarrod A. ; Donet, Jean ; Martin, Kyle S. ; Sharma, Ashish K. ; Chen, Xiaobin ; Zhang, Jiuzhi ; Cai, Jie ; Galarreta, Carolina A. ; Okutsu, Mitsuharu ; Du, Zhongmin ; Lira, Vitor A. ; Zhang, Mei ; Mehrad, Borna ; Annex, Brian H. ; Klibanov, Alexander L. ; Bowler, Russell P. ; Laubach, Victor E. ; Peirce, Shayn M. ; Yan, Zhen. / Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice. In: Free Radical Biology and Medicine. 2017 ; Vol. 113. pp. 212-223.
@article{a878687adb1a45bcbb77e4732448b2c3,
title = "Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice",
abstract = "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.",
keywords = "EcSOD, Endothelial activation, Endotoxemia, Free radicals, MODS, Oxidative stress, Parabiosis, Skeletal muscle, VCAM-1",
author = "Call, {Jarrod A.} and Jean Donet and Martin, {Kyle S.} and Sharma, {Ashish K.} and Xiaobin Chen and Jiuzhi Zhang and Jie Cai and Galarreta, {Carolina A.} and Mitsuharu Okutsu and Zhongmin Du and Lira, {Vitor A.} and Mei Zhang and Borna Mehrad and Annex, {Brian H.} and Klibanov, {Alexander L.} and Bowler, {Russell P.} and Laubach, {Victor E.} and Peirce, {Shayn M.} and Zhen Yan",
year = "2017",
month = "12",
doi = "10.1016/j.freeradbiomed.2017.09.029",
language = "English (US)",
volume = "113",
pages = "212--223",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice

AU - Call, Jarrod A.

AU - Donet, Jean

AU - Martin, Kyle S.

AU - Sharma, Ashish K.

AU - Chen, Xiaobin

AU - Zhang, Jiuzhi

AU - Cai, Jie

AU - Galarreta, Carolina A.

AU - Okutsu, Mitsuharu

AU - Du, Zhongmin

AU - Lira, Vitor A.

AU - Zhang, Mei

AU - Mehrad, Borna

AU - Annex, Brian H.

AU - Klibanov, Alexander L.

AU - Bowler, Russell P.

AU - Laubach, Victor E.

AU - Peirce, Shayn M.

AU - Yan, Zhen

PY - 2017/12

Y1 - 2017/12

N2 - 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.

AB - 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.

KW - EcSOD

KW - Endothelial activation

KW - Endotoxemia

KW - Free radicals

KW - MODS

KW - Oxidative stress

KW - Parabiosis

KW - Skeletal muscle

KW - VCAM-1

UR - http://www.scopus.com/inward/record.url?scp=85030860419&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030860419&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2017.09.029

DO - 10.1016/j.freeradbiomed.2017.09.029

M3 - Article

C2 - 28982599

AN - SCOPUS:85030860419

VL - 113

SP - 212

EP - 223

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

ER -