Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 11/21/2004
Publication Date: 2/10/2005
Citation: Elsasser, T.H., Schmidt, W.F., Kahl, S. 2005. Milk-fed farm and companion animals - basic aspects and practice for the future [abstract]. University of Berne, Switzerland, February 10-12, 2005. Interpretive Summary: Young animals have novel demands placed on them to adjust to their new environment. It is especially important that the circulation be maintained, that oxygenation of blood and tissues be efficient, and that the metabolic needs of tissues be fulfilled. To accomplish this, the young animal needs to establish the functionality of biological processes that coordinate all these events. It is recognized now that a high level of neonatal production of nitric oxide may help this process along. Nitric oxide relaxes blood vessels to increase blood flow and nutrient and oxygen delivery to tissues. We have identified additional properties of nitric oxide that cause the nitration of specific proteins in the neonate. These nitrations change the activity of these proteins and can function as a regulatory mechanism to let the neonate function efficiently until more sophisticated forms of regulation can be established. Understanding these new nitration mechanisms may permit researchers to develop strategies to make the transition from life in the uterus to life in the ambient environment less stressful to the infant.
Technical Abstract: At birth, neonatal animals show signs of significant activation of the nitric oxide production cascade as evidenced by millimolar concentrations of nitrate, the stabile end product of NO decay. The biological reason for this extensive activation of this axis is not known, but may relate to homeostatic adjustments for the neonate as its existence transforms from the protected uterine environment to the ambient world. Interestingly, however, complementary recent evidence suggests that high levels of nitration and thiol nitrosylation of proteins are present at this time and that these chemical modifications may be more specific than previously considered. It is well recognized that many functional aspects of the growth hormone (GH) axis are not active at this time, at least with regard to the capacity for GH to regulate insulin-like growth factor-1 (IGF-1) production. Several explanations have been postulated to explain this refractory GH state, including low GH receptor numbers and generalized failure to induce IGF-1 mRNA. However, we have detected in the neonate an increased level of a specific nitration in the GH signal transduction pathway that regulates GH functionality. Based on high field magnetic resonance spectroscopic analysis of a nitrated region of the tyrosine phosphorylation activation motif of JAK-2 kinase, the key GH receptor, we have evidence that the specific 3'-nitration of the tyrosine phenolic rings located at the 1007 and 1008 positions spatially compromises the ability for the phosphate group to be added at the adjacent 'ortho position thus preventing the activation of JAK-2 kinase and blocking the GH signal. The data suggest that nitration of GH signal transduction proteins may contribute to neonatal GH refractoriness.