Inducible nitric oxide synthase activity mediates TNF-α-induced endothelial cell dysfunction.

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Metabolomics

Background:

• Vascular endothelial dysfunction is linked to inducible nitric oxide synthase (iNOS) and atherosclerosis.
• Tumor necrosis factor-α (TNF-α) exacerbates endothelial injury via iNOS, reactive oxygen species (ROS), and nuclear factor-κB (NF-κB) activation.

Purpose of the Study:

• To investigate the role of iNOS in TNF-α-induced vascular endothelial dysfunction.
• To elucidate the molecular and metabolic mechanisms involved.

Main Methods:

• Used ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry and multivariate data analysis to profile metabolites in human umbilical vein endothelial cells (HUVECs).
• Employed molecular biology techniques to assess protein expression and cellular responses.

Main Results:

• iNOS deficiency reversed TNF-α-induced pathological changes, including reduced ROS and NF-κB activation.
• iNOS deficiency decreased TNF-α-mediated upregulation of tumor necrosis factor receptor-2 (TNFR-2), p-IκBα, IL-6, CD31, ICAM-1, and VCAM-1.
• Identified metabolic biomarkers in pathways like glycosylphosphatidylinositol-anchor biosynthesis and lipid metabolism associated with endothelial dysfunction.

Conclusions:

• iNOS plays a critical role in TNF-α-induced endothelial dysfunction.
• iNOS deficiency attenuates endothelial dysfunction by modulating TNFR-2, vascular adhesion molecules, and ROS levels through metabolic alterations.