Related Experiment Video
Updated: Feb 21, 2026
En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries
Published on: February 25, 2016
Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ
Jarrod A Call1, Jean Donet1, Kyle S Martin2
1Center 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.
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.
Insights
Enhanced extracellular superoxide dismutase (EcSOD) in skeletal muscle protects against multiple organ dysfunction syndrome (MODS). This antioxidant enzyme reduces mortality and organ damage by preventing endothelial activation and inflammatory cell adhesion during endotoxemia.
Area of Science:
- Biochemistry
- Physiology
- Immunology
Background:
- Multiple organ dysfunction syndrome (MODS) is a leading cause of death in critically ill patients.
- Oxidative stress and endothelial activation are critical early events in MODS pathogenesis.
- Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme with a potential role in mitigating organ damage.
Purpose of the Study:
- To investigate the protective role of enhanced skeletal muscle EcSOD expression against endotoxemia-induced MODS.
- To elucidate the underlying mechanisms by which EcSOD confers protection.
Main Methods:
- Generation of skeletal muscle-specific EcSOD-overexpressing transgenic (TG) mice.
- Induction of endotoxemia using lipopolysaccharide (LPS) in TG and wild-type (WT) mice.
- Assessment of mortality, organ damage, and inflammatory markers.
- Heterochronic parabiosis experiments and analysis of a human EcSOD polymorphism (R213G).
Main Results:
- TG mice exhibited significantly reduced mortality and organ damage compared to WT mice following LPS injection.
- EcSOD redistributed from skeletal muscle to peripheral organs, enriching the vascular endothelium.
- WT mice parabiosed with TG mice showed protection, while mice with the R213G mutation showed exacerbated damage.
- EcSOD inhibited vascular cell adhesion molecule 1 expression and leukocyte adhesion in vital organs.
Conclusions:
- Enhanced skeletal muscle EcSOD expression provides significant protection against endotoxemia-induced MODS.
- EcSOD's protective effects are mediated by inhibiting endothelial activation and inflammatory cell infiltration.
- Targeting EcSOD expression may represent a novel therapeutic strategy for MODS.
