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.

Figure 1

Nitrates, ADMA, and endothelin-1 (ET-1) concentrations of plasma from yaks and bovines. Nitrate concentration, measured by Griess method, showed no significant differences between yaks (n = 12) and bovines (n = 6) (a). ADMA concentration, measured by ELISA, was significantly lower in yaks (n = 19) than bovines (n = 11) (b), and ET-1 concentration was significantly higher in yaks (n = 13) than bovines (n = 10) (c). Data are expressed as mean ± SD. ^∗ P < 0.05 versus bovine.

Figure 2

Western blot analysis of eNOS, DDAH I, and DDAH II protein in lungs from yaks and bovines. The photomicrograph shown is a representative image from the experiments, and the bar graph shows the density ratios of eNOS, DDAH I, and DDAH II protein bands relative to those from bovines. The eNOS, DDAH I, and DDAH II protein expression was apparently increased in lungs from yaks compared with those from bovines. Data are expressed as mean ± SD (n = 2).

Figure 3

DDAH activity in lungs from yaks and bovines. The bar graph shows DDAH I activity in the lungs from yaks and bovines. The DDAH activity is significantly increased in lungs from yaks compared with those from bovines. Data are expressed as mean ± SD (n = 6). ^∗ P < 0.05 versus bovine.