Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

Abstract

Background-Liver ischemia reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. Nitric oxide (NO), shown to have protective effects in I/R, is produced by nitric oxide synthase (NOS) from the substrate arginine. The purpose of this study was to determine if nor-NOHA, a novel arginase inhibitor, would be able to increase circulating arginine levels and decrease hepatic damage following warm I/R.

Mouse hepatocytes and LSEC proteome reveal novel mechanisms of ischemia/reperfusion damage and protection by A2aR stimulation

“…Notably, among the 28 metabolic proteins identified, only 14 were already connected to IR and preconditioning (FABPL, ATPB, FABPI, ENOA, ATPA, ARGI1, ALDOB, ETFA, THIM, CPSM, TPIS, OTC, HINT, FABP5) [5,[24][25][26][28][29][30][31][32], while the others are completely new (GLYC, IDHC, KPYR, DHSO, FAAA, S2542, PGK1, CLC4F, ODBA, NDKB, ATP5H, PROSC, ECH1, AL4A1).…”

Angiotensin II limits NO production by upregulating arginase through a p38 MAPK–ATF-2 pathway

“…Elevated arginase activity has been associated with cardiovascular pathologies such as hypertension, diabetes, atherosclerosis, ischemic reperfusion injury, erectile dysfunction and sickle cell anemia (Bagnost et al, 2008; Bivalacqua et al, 2007; Jeyabalan et al, 2008; Morris et al, 2005; Romero et al, 2008). In these conditions, elevation of arginase has been shown to mediate vascular dysfunction through limiting nitric oxide (NO) production or availability.…”

Single- and multiple-dose pharmacokinetics of arginase inhibitor Nω-hydroxy-nor-L-arginine, and its effect on plasma amino acids concentrations in Wistar rats

“…Results of published studies suggest that an increased expression and activity of arginases is causally involved in the pathophysiology of various diseases and conditions like increased vascular resistance and cardiac fibrosis in hypertension (Bagnost et al 2010), coronary artery microvascular dysfunction in diabetes (Gronros et al 2011), myocardial (Jung et al 2010) and hepatic (Jeyabalan et al 2008) ischemia-reperfusion injury, airway hyperresponsiveness and remodelling in bronchial asthma (Zimmermann and Rothenberg 2006;Vonk et al 2010), and immune cell dysfunction (Maarsingh et al 2008;Bratt et al 2010;Takahashi et al 2010). The widely accepted theory is that overexpression of arginase I or II reduces NO synthesis via effective competition with NOS for L-arginine, increases superoxide generation by NOS, and enhances polyamine synthesis and cell proliferation (Morris 2009).…”

“…As compared to NOHA, nor-NOHA is a 40-times more potent inhibitor of arginases but it does not serve as a substrate for NOS (Moali et al 1998;Jeyabalan et al 2008;Jung et al 2010). Several published studies brought the evidence of therapeutic effects of nor-NOHA in rodent models for various diseases.…”