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.

Diabetes-induced Coronary Vascular Dysfunction Involves Increased Arginase Activity

“…42,43 Active RhoA, in turn, has been shown to activate arginase. 32,33 The lineage of events appears to be oxidative stress3activation of RhoA3activation and enhanced expres- sion of arginase. Further study is needed to elucidate other molecular mediators in this pathway.…”

“…31 Elevation of arginase activity has been shown to involve activation of the RhoA pathway in endothelial cells. 32,33 Based on this and the evidence above that both diabetes and L-arginine treatment can increase arginase activity, we hypothesized that diabetes-induced vascular dysfunction involves increased levels of arginase activity and that simvastatin prevents vascular dysfunction because it reduces arginase activity. We tested this hypothesis and investigated the protective effects of statin treatment and L-citrulline supplementation in studies using STZ diabetic rats and high glucose (HG)-treated endothelial cells.…”

Multiple Pathogenic Roles of Microvasculature in Inflammatory Bowel Disease: A Jack of All Trades

“…19,20 Recent evidence also suggests that increased arginase activity in HIMECs exposed to an inflammatory milieu contributes to the loss of NO production. 21 Apart from classic adhesion molecules, the unique CX 3 C chemokine fractalkine (FKN), which acts as an adhesion molecule, has been shown to be up-regulated in the endothelium of both CD and UC patients. 22 Indeed, HIMECs isolated from IBD patients display an increased expression of FKN after stimulation with the combination of interferon ␥ (IFN-␥) and TNF-␣ compared with HIMECs derived from control subjects.…”

Mechanisms of Endothelial Dysfunction Induced by Aging

“…14 However, a recent study demonstrated that arginase plays an important role in loss of NO and pathogenesis of endothelial dysfunction in human blood vessels exposed to proinflammatory conditions in vivo. 15 This observation together with reported propensity of aged blood vessels to express higher levels of proinflammatory cytokines 16 suggest that contribution of arginase to endothelial dysfunction may depend on degree of vascular inflammatory response to aging. Further in vivo studies with selective inhibitors of arginase I, as well as better understanding of the mechanisms involved in regulation of arginase in aging human endothelium, will define importance and therapeutic value of arginase inhibition in prevention and treatment of cardiovascular disease.…”