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1 Medical College of Wisconsin, Milwaukee, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: prafiee{at}mcw.edu.
Objective: 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 (CD) and ulcerative colitis (UC)). 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 NOS for the common substrate L-arginine. We characterized AR expression in IBD microvessels and endothelial cells and it contribution to decreased ·NO production.
Methods: AR expression was assessed in resected gut tissues and human intestinal microvascular endothelial cells (HIMEC).
Results: AR expression significantly increased in both UC and CD microvessels and submucosal tissues compared to normal. TNF-
/LPS 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-
/LPS 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 as compared with normal control gut tissue. Functionally, inhibition of AR activity decreased leukocyte binding to HIMEC in an adhesion assay.
Conclusions: Loss of ·NO production in IBD microvessels is linked to enhanced levels of AR in intestinal endothelial cells exposed to chronic inflammation in vivo.
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