Tags

Type your tag names separated by a space and hit enter

Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease.

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.

Authors+Show Affiliations

Dept. of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17218473

Citation

Horowitz, Scott, et al. "Increased Arginase Activity and Endothelial Dysfunction in Human Inflammatory Bowel Disease." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 292, no. 5, 2007, pp. G1323-36.
Horowitz S, Binion DG, Nelson VM, et al. Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 2007;292(5):G1323-36.
Horowitz, S., Binion, D. G., Nelson, V. M., Kanaa, Y., Javadi, P., Lazarova, Z., ... Rafiee, P. (2007). Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease. American Journal of Physiology. Gastrointestinal and Liver Physiology, 292(5), pp. G1323-36.
Horowitz S, et al. Increased Arginase Activity and Endothelial Dysfunction in Human Inflammatory Bowel Disease. Am J Physiol Gastrointest Liver Physiol. 2007;292(5):G1323-36. PubMed PMID: 17218473.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease. AU - Horowitz,Scott, AU - Binion,David G, AU - Nelson,Victoria M, AU - Kanaa,Yasmin, AU - Javadi,Pooria, AU - Lazarova,Zelmira, AU - Andrekopoulos,Christopher, AU - Kalyanaraman,Balaraman, AU - Otterson,Mary F, AU - Rafiee,Parvaneh, Y1 - 2007/01/11/ PY - 2007/1/16/pubmed PY - 2007/7/7/medline PY - 2007/1/16/entrez SP - G1323 EP - 36 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am. J. Physiol. Gastrointest. Liver Physiol. VL - 292 IS - 5 N2 - 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. SN - 0193-1857 UR - https://www.unboundmedicine.com/medline/citation/17218473/Increased_arginase_activity_and_endothelial_dysfunction_in_human_inflammatory_bowel_disease_ L2 - http://www.physiology.org/doi/full/10.1152/ajpgi.00499.2006?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -