Association of Genes of the NO Pathway with Altitude Disease and Hypoxic Pulmonary Hypertension.

Juliane Hannemann,Lena Schmidt-Hutten,Patricia Siques,Rainer Böger,Julio Brito,Julia Zummack

doi:10.3390/jcm10245761

Abstract

Chronic intermittent hypoxia leads to high-altitude pulmonary hypertension, which is associated with high asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis. Therefore, we aimed to understand the relation of single nucleotide polymorphisms in this pathway to high-altitude pulmonary hypertension (HAPH). We genotyped 69 healthy male Chileans subjected to chronic intermittent hypoxia. Acclimatization to altitude was determined using the Lake Louise Score and the presence of acute mountain sickness. Echocardiography was performed after six months in 24 individuals to estimate pulmonary arterial pressure. The minor allele of dimethylarginine dimethylaminohydrolase (DDAH)1 rs233112 was associated with high-baseline plasma ADMA concentration, while individuals homozygous for the major allele of DDAH2 rs805304 had a significantly greater increase in ADMA during chronic intermittent hypoxia. The major allele of alanine glyoxylate aminotransferase-2 (AGXT2) rs37369 was associated with a greater reduction of plasma symmetric dimethylarginine (SDMA). Several genes were associated with high-altitude pulmonary hypertension, and the nitric oxide synthase (NOS)3 and DDAH2 genes were related to acute mountain sickness. In conclusion, DDAH1 determines baseline plasma ADMA, while DDAH2 modulates ADMA increase in hypoxia. AGXT2 may be up-regulated in hypoxia. Genomic variation in the dimethylarginine pathway affects the development of HAPH and altitude acclimatization.

Highlights

Chronic exposure to global hypoxia, e.g., at high altitude, may cause generalized hypoxic pulmonary vasoconstriction, leading to pulmonary arterial hypertension [1,2]. This pulmonary vasoconstriction is partly caused by diminished endothelium-dependent, nitric oxide (NO)-mediated vasodilation, a molecular response that is in sharp contrast to up-regulation of NO synthase in the systemic arterial endothelium in hypoxia [3–5]
We previously demonstrated that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis, is up-regulated in chronic intermittent hypoxia (CIH), a condition affecting large numbers of individuals living at sea level and working at high altitude, e.g., in the Chilean mining areas in the Andes [1]
In a prospective study among 123 healthy males, we showed that ADMA is elevated during six months of chronic intermittent hypoxia, and that elevated ADMA concentration at baseline is a predictor of high-altitude pulmonary hypertension incidence [8]

Summary

Introduction

Chronic exposure to global hypoxia, e.g., at high altitude, may cause generalized hypoxic pulmonary vasoconstriction, leading to pulmonary arterial hypertension [1,2]. We previously demonstrated that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis, is up-regulated in chronic intermittent hypoxia (CIH), a condition affecting large numbers of individuals living at sea level and working at high altitude, e.g., in the Chilean mining areas in the Andes [1]. These data are in line with those derived from animal models of chronic hypoxia [6,7]. In a prospective study among 123 healthy males, we showed that ADMA is elevated during six months of chronic intermittent hypoxia, and that elevated ADMA concentration at baseline is a predictor of high-altitude pulmonary hypertension incidence [8]

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