Septic shock is correlated with asymmetrical dimethyl arginine levels, which may be influenced by a polymorphism in the dimethylarginine dimethylaminohydrolase II gene: a prospective observational study

Abstract

Introduction Asymmetrical dimethyl arginine (ADMA) is an endogenous non-selective inhibitor of nitric oxide synthase that may influence the severity of organ failure and the occurrence of shock secondary to an infectious insult. Levels may be genetically determined by a promoter polymorphism in a regulatory gene encoding dimethylarginine dimethylaminohydrolase II (DDAH II), which functions by metabolising ADMA to citrulline. The aim of this study was to examine the association between ADMA levels and the severity of organ failure and shock in severe sepsis and also to assess the influence of a promoter polymorphism in DDAH II on ADMA levels.

Dimethylarginine Dimethylaminohydrolase 2 Regulates Nitric Oxide Synthesis and Hemodynamics and Determines Outcome in Polymicrobial Sepsis

“…18 It has been suggested that DDAH2 may also play a role in both the physiological regulation of the cardiovascular system and also in the pathophysiological response to sepsis. 13 This is the first study to demonstrate a physiological role for DDAH2 and shows that knockout of the enzyme results in an animal with mild hypertension seen during periods of activity that is associated with elevated methylarginine concentrations and reciprocal reductions in systemic NO levels. This study also shows for the first time that in polymicrobial sepsis, Ddah2 deletion has a profound impact on NO production, immune function, and outcome, and it is macrophage DDAH2 that is a key regulator of this effect.…”

“…The DDAH2 gene is found in the major histocompatibility complex III region 16 and polymorphisms of the promoter region of the gene have been shown to affect circulating ADMA levels and illness severity in both adult and pediatric populations with severe sepsis, 13,14 however, the small number of subjects examined in these studies necessitates cautious interpretation of these data. Given these associations, we went on to explore the functional role of Ddah2 in sepsis using highly specific genetic modifications.…”

“…13,14 This may also provide a link between poor outcome in sepsis and patients with established cardiovascular disease with associated derangement of the ADMA regulatory pathway. 28,29 Exploration of these hypotheses through large-scale clinical studies is warranted.…”

“…[12][13][14][15] ADMA is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to dimethylamine and citrulline. 16 Two isoforms of DDAH exist which have differing distributions throughout the body.…”

“…20 Its temporal and spatial colocalization with DDAH1 in the vasculature suggests that it may be involved in regulating vascular tone. Furthermore, its genetic location in the major histocompatibility complex III region of chromosome 6 16 , the fact that it is the only isoform expressed in immune cells 17 together with preliminary data demonstrating an association between human DDAH2 promoter polymorphisms and outcome in sepsis 13,14 has led to the suggestion that DDAH2 may play a role in regulating the immune response.…”