Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease

Area of Science:

• Vascular Biology
• Gastroenterology
• Immunology

Background:

• Nitric oxide (NO) is crucial for vascular homeostasis, and its loss is linked to vascular pathophysiology.
• Decreased NO production is observed in the chronically inflamed gut blood vessels of inflammatory bowel disease (IBD).
• The mechanisms behind reduced NO production in IBD gut microvessels are not fully understood.

Purpose of the Study:

• To investigate the role of arginase (AR) expression and activity in IBD-associated microvascular dysfunction.
• To characterize AR's contribution to decreased NO production in the context of chronic gut inflammation.

Main Methods:

• AR expression was assessed in resected IBD gut tissues and human intestinal microvascular endothelial cells (HIMEC).
• AR activity, mRNA, and protein levels were measured in HIMEC stimulated with TNF-alpha/lipopolysaccharide.
• The RhoA/ROCK pathway's involvement in regulating AR expression was examined using specific inhibitors.
• Leukocyte adhesion assays were performed to assess functional consequences.

Main Results:

• AR expression was significantly increased in microvessels and submucosal tissues of both ulcerative colitis and Crohn's disease patients compared to controls.
• TNF-alpha/lipopolysaccharide stimulation elevated AR activity, mRNA, and protein expression in HIMEC.
• The RhoA/ROCK pathway mediated the inflammatory induction of AR expression.
• Higher AR and RhoA activity were found in IBD submucosal tissues, and AR inhibition reduced leukocyte binding to HIMEC.

Conclusions:

• Enhanced arginase (AR) levels in intestinal endothelial cells contribute to the loss of nitric oxide (NO) production in IBD microvessels.
• Chronic inflammation in IBD upregulates AR via the RhoA/ROCK pathway, impairing vascular function.
• Targeting AR may represent a therapeutic strategy for IBD-related vascular complications.