Endogenous Asymmetric Dimethylarginine Pathway in High Altitude Adapted Yaks.

Shiro Mizuno,Elnura Taalaibekova,Zamirbek Baiserkeev,Hirohisa Toga,Baktybek Kojonazarov,Almaz Aldashev,Akio Sakai,Takeshi Ishizaki,Jainagul Isakova

doi:10.1155/2015/196904

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.

Highlights

It is well known that endogenous nitric oxide (NO) plays a pivotal role in maintaining the low pulmonary vascular tone patients with pulmonary hypertension [1]
The dimethylarginine dimethylaminohydrolases (DDAH) activity has a protective role in insulin resistance [6, 7] and progression of chronic kidney disease, which are both associated with reduced level of asymmetric dimethylarginine (ADMA) and increased endogenous NO production [8, 9]
We find increased DDAH expression and activity associated with low levels of plasma ADMA in yaks

Summary

Introduction

It is well known that endogenous nitric oxide (NO) plays a pivotal role in maintaining the low pulmonary vascular tone patients with pulmonary hypertension [1]. A reduced expression or pharmacological inhibition of DDAH results in elevated levels of ADMA associated with decreased reaction of NO-mediated vasodilation [10] which supports the idea that local tissue DDAH activity plays an important role in the maintenance of vascular tone and NOS activity via ADMA production. We previously reported an enhanced effect of NOS inhibition in the yak pulmonary circulation [32], consistent with an augmented production of NO in yaks living at high altitude. Because of these previous findings, we hypothesized that elevated activity of DDAH in the lung tissue, which suppresses ADMA expression, could be a regulatory factor of the pulmonary vascular tone in yaks.

Materials and Methods

Results

Discussion