Faculty Collaboration Database

Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2007 May;292(5):G1323-36

Date

01/16/2007

Pubmed ID

17218473

DOI

10.1152/ajpgi.00499.2006

Scopus ID

2-s2.0-34347379767 (requires institutional sign-in at Scopus site)   114 Citations

Abstract

Nitric oxide (.NO) generation from conversion of l-arginine to citrulline by nitric oxide synthase isoforms plays a critical role in vascular homeostasis. Loss of .NO is linked to vascular pathophysiology and is decreased in chronically inflamed gut blood vessels in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis). Mechanisms underlying decreased .NO production in IBD gut microvessels are not fully characterized. Loss of .NO generation may result from increased arginase (AR) activity, which enzymatically competes with nitric oxide synthase for the common substrate l-arginine. We characterized AR expression in IBD microvessels and endothelial cells and its contribution to decreased .NO production. AR expression was assessed in resected gut tissues and human intestinal microvascular endothelial cells (HIMEC). AR expression significantly increased in both ulcerative colitis and Crohn's disease microvessels and submucosal tissues compared with normal. TNF-alpha/lipopolysaccharide increased AR activity, mRNA and protein expression in HIMEC in a time-dependent fashion. RhoA/ROCK pathway, a negative regulator of .NO generation in endothelial cells, was examined. The RhoA inhibitor C3 exoenzyme and the ROCK inhibitor Y-27632 both attenuated TNF-alpha/lipopolysaccharide-induced MAPK activation and blocked AR expression in HIMEC. A significantly higher AR activity and increased RhoA activity were observed in IBD submucosal tissues surrounding microvessels compared with normal control gut tissue. Functionally, inhibition of AR activity decreased leukocyte binding to HIMEC in an adhesion assay. Loss of .NO production in IBD microvessels is linked to enhanced levels of AR in intestinal endothelial cells exposed to chronic inflammation in vivo.

Author List

Horowitz S, Binion DG, Nelson VM, Kanaa Y, Javadi P, Lazarova Z, Andrekopoulos C, Kalyanaraman B, Otterson MF, Rafiee P

Authors

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Mary F. Otterson MS, MD Emeritus Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ADP Ribose Transferases
Amides
Arginase
Arginine
Botulinum Toxins
Cell Adhesion Molecules
Crohn Disease
Endothelium
Humans
Inflammatory Bowel Diseases
Intestinal Mucosa
Intracellular Signaling Peptides and Proteins
Lipopolysaccharides
MAP Kinase Signaling System
Nitric Oxide
Pyridines
RNA, Messenger
Tumor Necrosis Factor-alpha
Valine
rho-Associated Kinases
rhoA GTP-Binding Protein