NOS2 deficiency increases intestinal metabolism both in nonstimulated and endotoxemic mice

Abstract

Animal studies have suggested that nitric oxide (NO) synthases (NOS) play a role in the regulation of protein metabolism in endotoxemia. We therefore investigated the role of inducible NOS (NOS2) on intestinal protein and neuronal NOS (NOS1) and endothelial NOS (NOS3) on amino acid metabolism. Three groups of mice were studied: 1) wild-type (WT), 2) NOS2 knockout (NOS2-KO), and 3) NOS2-KO + N(omega)-nitro-l-arginine methyl ester (NOS2-KO + l-NAME), both in nonstimulated and LPS-treated conditions. By infusion of the stable isotopes l-[phenyl-(2)H(5)]Phe, l-[phenyl-(2)H(2)]Tyr, l-[guanidino-(15)N(2)]Arg, and l-[ureido-(13)C; (2)H(2)]citrulline (Cit), intestinal protein, amino acid, and Arg/NO metabolism were studied on the whole body level and across intestine. In nonstimulated situations, NOS2 deficiency increased whole body protein turnover and intestinal Gln uptake and Cit production. In NOS2-KO + l-NAME, the above-mentioned changes were reversed. After LPS in WT, whole body NO and Cit production increased. In contrast to this, LPS decreased net intestinal Gln uptake, whole body NO, and Cit production in NOS2-KO mice. Treatment of NOS2-KO + l-NAME with LPS was lethal in eight of eleven mice (73%). The surviving mice in this group showed a major drop in intestinal protein breakdown and synthesis to almost zero. Thus both in baseline conditions and during endotoxemia, the absence of NOS2 upregulated NOS1 and/or NOS3, which increased intestinal metabolism. The drop in intestinal protein metabolism in the endotoxemic NOS2-KO + l-NAME group might play a role in mortality in that group.

The role of NOS2 and NOS3 in renal protein and arginine metabolism during early endotoxemia in mice

“…The discrepancy between whole body and renal metabolism might indicate that other organs, e.g., the gut, importantly downregulate their protein metabolism during early endotoxemia. In male C57BL6/J mice, we indeed observed a reduction in gut protein breakdown and synthesis (32).…”

“…Moreover, the absence of an increase in plasma nitrate in NOS2 Ϫ/Ϫ mice may also be related to an effect on intestinal bacterial nitrate production in these mice. In addition, strain and sex differences seem to exist, since we observed, using the same experimental protocol, a 2.5-fold increase in systemic NO synthesis after LPS in Swiss mice (12) and a similar increase in male C57BL6/J mice (32).…”

The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis

“…LPS and endotoxin treatment in cell culture and rats respectively, induce Nos2 while decreasing Nos3 protein and mRNA expression [28–30]. Nos2 knockout mice show increased NOS1 and/or NOS3‐related activity, while in mice infected with Trypanosoma cruzi Ca 2+ ‐dependent (NOS1/NOS3) activity is decreased whereas Ca 2+ ‐independent (NOS2) activity increased [31,32]. Studies in endothelial cells demonstrated a decrease in NOS3 mRNA expression as a result of increased degradation [30,33].…”

Expression profile of Nanos2 gene in dairy goat and its inhibitory effect on Stra8 during meiosis

“…In the mouse testes, there are two types of spermatogonium, undifferentiated and differentiating ones (2). Undifferentiated spermatogonia, also termed spermatogonial stem cells (SSCs), initiate spermatogenesis; they include type Asingle (As, isolated single cell), Apaired (Apr, chains of two cells) and Aaligned (Aal, chains of 4,8,16 or occasionally 32 cell) spermatogonia (3). Germ cell-specific protein Nanos2 is expressed in embryonic germ cells and has an important effect on survival and maintenance of germ cells (4)(5)(6).…”