Plasmatic Concentrations of ADMA and Homocystein in Llama (Lama glama) and Regulation of Arginase Type II: An Animal Resistent to the Development of Pulmonary Hypertension Induced by Hypoxia

Abstract

There are animal species that have adapted to life at high altitude and hypobaric hypoxia conditions in the Andean highlands. One such species is the llama (Lama glama), which seem to have developed efficient protective mechanisms to avoid maladaptation resulting from chronic hypoxia, such as a resistance to the development of hypoxia -induced pulmonary hypertension. On the other hand, it is widely known that different models of hypertension can arise as a result of changes in endothelial function. The respect, one of the common causes of deregulation in endothelial vasodilator function have been associated with down-regulation of the NO synthesis and an increase in plasma levels of asymmetric dimethylarginine (ADMA) and homocysteine. Additionally, it is also known that NO production can be regulated by plasma levels of L-arginine as a result of the competition between nitric oxide synthase (NOS) and arginase. The objective of this study, was to determine the baseline concentrations of ADMA and homocysteine in llama, and to evaluate their effect on the arginase pathway and their involvement in the resistance to the development of altitude-induced pulmonary hypertension. METHOD: Lowland and highland newborn sheep and llama were investigated near sea level and at high altitude. Blood determinations of arterial blood gases, ADMA and homocysteíne are made and the effect of these on the arginase activity was evaluated. RESULTS: The basal concentrations of ADMA and homocysteine were determined in llama, and they were found to be significantly lower than those found in other species and in addition, the exposure to hypoxia is unable to increase its concentration. On the other hand, it was observed that the llama exhibited 10 times less arginase II activity as compared to sheep, and the expression was not induced by hypoxia. Finally, ADMA y Hcy, has no effect on the type II arginase pathway. CONCLUSION: Based on our results, we propose that low concentrations of ADMA and homocysteine found in llamas, the low expression of arginase type II, DDAH-2 and CBS, as well as its insensitivity to activation by homocysteine could constitute an adaptation mechanism of these animals to the hypoxia.

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

“…A variety of single nucleotide polymorphisms in genes relating to nitric oxide bioavailability were significantly associated with high-altitude pulmonary hypertension. These data support a role of the L-arginine-dimethylarginine-NO pathway in the long-term adaptation to repetitive exposure towards high altitude, in line with previous reports comparing yaks with cattle [30] and lama with sheep [31]. Persistent high-altitude pulmonary hypertension during chronic hypoxia and, importantly, also during chronic intermittent hypoxia, may lead to serious health consequences by causing right ventricular hypertrophy and, finally, right heart failure [1].…”

Elevated serum circ_0068481 levels as a potential diagnostic and prognostic indicator in idiopathic pulmonary arterial hypertension

“…Right ventricular dimension, tricuspid annular motion velocities, and tricuspid regurgitation have been associated with right ventricular enlargement and dysfunction, 20 whilst pulmonary systolic blood pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, mean right atrial pressure, and pulmonary artery oxygen saturation have been associated with IPAH development. Serum NT-proBNP, H 2 S, and 6MWD have been reported to correlate with IPAH progression and RHF, 21–23 suggesting that circ_0068481 may be associated with RHF in patients with IPAH. In this study, we found that circ_0068481 expression correlated significantly with RHF and the death of patients with IPAH, further suggesting that circ_0068481 plays an important role in regulating IPAH progression.…”

Metabolism of asymmetric dimethylarginine in hypoxia: from bench to bedside

“…In another study, Lopez et al. 46 studied expression and activity of components of the L-arginine–ADMA–NO pathway between newborn llamas and sheep at high and low altitude. Newborn sheep had significantly elevated ADMA plasma concentration and decreased DDAH2 mRNA expression in lung tissue as compared to sheep born in lowland.…”

“…These results may explain previously reported differences in the pulmonary endothelial response to acetylcholine between yak and domestic cow, suggesting that pulmonary endothelial function and structure critically determine adaptation to life at high altitude. 45 In another study, Lopez et al 46 studied expression and activity of components of the L-arginine-ADMA-NO pathway between newborn llamas and sheep at high and low altitude. Newborn sheep had significantly elevated ADMA plasma concentration and decreased DDAH2 mRNA expression in lung tissue as compared to sheep born in lowland.…”