Endogenous Asymmetric Dimethylarginine Pathway in High Altitude Adapted Yaks

Abstract

Hypoxia-induced and high altitude pulmonary hypertension are a major problem in the mountain areas of the world. The asymmetric methylarginines (ADMA) inhibit nitric oxide (NO) synthesis by competing with L-arginine, and high levels of plasma ADMA predict adverse outcomes in pulmonary hypertension. However, little is known about the regulation of the ADMA-NO pathway in animals adapted to high altitudes. We measured the plasma ADMA concentration, endothelial NO synthase (eNOS), dimethylarginine dimethylaminohydrolases (DDAH) protein expression, and DDAH activities in the lungs from yaks. Although the yaks are hypoxemic, cardiac function and pulmonary arterial pressures are almost normal, and we found decreased DDAH expression and activity in association with reduced plasma ADMA concentrations. The eNOS expression was significantly higher in yaks. These results indicate that augmented endogenous NO activity in yaks through the ADMA-DDAH pathway and eNOS upregulation account for the low pulmonary vascular tone observed in high altitude adapted yaks.

Long-Term Intermittent Exposure to High Altitude Elevates Asymmetric Dimethylarginine in First Exposed Young Adults

“…The pattern of changes in biomarkers measured in the study presented here (elevation of ADMA and L-NMMA, no significant change in SDMA) suggests that dysregulation of DDAH may also occur in high altitude-induced hypoxia in humans. This hypothesis is supported by the study of Mizuno et al ( 2015 ), who demonstrated reduced ADMA and enhanced DDAH activity in lungs of yaks—animals adapted to high altitude—as opposed to bovine. Furthermore, Ali et al ( 2012 ) recently reported that elevation of ADMA, among other biomarkers, was associated with high-altitude pulmonary edema in first-time high-altitude sojourners.…”

“…There is little published information on the possible role of ADMA in high altitude-induced hypobaric hypoxia in humans and its association with altitude diseases and acclimatization. Recently, one study in yaks demonstrated a low plasma ADMA concentration as a result of increased expression and activity of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA (Mizuno et al, 2015 ). We have recently shown that ADMA is also increased in rats that are exposed to chronic intermittent hypoxia (Lüneburg et al, 2016 ).…”

Analysis of Hematological Traits in Polled Yak by Genome-Wide Association Studies Using Individual SNPs and Haplotypes

“…Yak ( Bos grunniens ) is an iconic symbol of the Qinghai–Tibet Plateau and adjacent high-altitude areas [1]. This region is well known for its high-altitude, pristine natural environment, and extreme seasonal changes [2]. During the early Holocene period, the ancient Qiang people began to domesticate wild yaks [3,4].…”

Whole‐genome analysis identifying candidate genes of altitude adaptive ecological thresholds in yak populations

“…Previously, as a representative species of plateau adaptation, yak were widely used to study plateau adaptability (e.g., Ishizaki et al, ; Mizuno et al, ) and especially to identify altitude‐adapted genes by comparing genomic interspecies differences (e.g., Wang, Zan, & Zhang, ). However, recent research has mostly focused on investigating the altitude‐adapted genes within species (e.g., Jin et al, ; Tang et al, ).…”