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Free Radic Biol Med. 2017 Dec;113:212-223. doi: 10.1016/j.freeradbiomed.2017.09.029. Epub 2017 Oct 2.

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

Author information

1
Center for Skeletal Muscle Research at Robert Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Departments of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
2
Departments of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
3
Departments of Surgery, University of Virginia, Charlottesville, VA 22908, USA.
4
Center for Skeletal Muscle Research at Robert Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Department of Cardiology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province 410008, China.
5
Center for Skeletal Muscle Research at Robert Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Department of Critical Care Medicine and Institute of Critical Care Medicine, First Affiliate Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, Liaoning Province 116011, China.
6
Center for Skeletal Muscle Research at Robert Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Department of Infectious Disease, First Affiliate Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province 210029, China.
7
Departments of Pediatrics, University of Virginia, Charlottesville, VA 22908, USA.
8
Departments of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
9
Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, CO, USA.
10
Center for Skeletal Muscle Research at Robert Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Departments of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Departments of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA; Departments of Molecular Physiology & Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: zhen.yan@virginia.edu.

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

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