Scientific Article Association Between Plasma N-Acylethanolamides and High Hemoglobin Concentration in Southern Peruvian Highlanders Dulce E. Alarco ´ n-Yaquetto, 1 Lidia Caballero, 2,3 and Gustavo F. Gonzales 1,2,4 Abstract Alarco ´n-Yaquetto, Dulce E., Lidia Caballero, and Gustavo F. Gonzales. Association between plasma N- acylethanolamides and high hemoglobin concentration in Southern Peruvian highlanders. High Alt Med Biol 00:000– 000, 2017.—High-altitude (HA) hypoxia is a stressful condition endured by organisms through different mechanisms. Failing to adapt to chronic HA exposure leads to a disease called chronic mountain sickness (CMS) characterized by excessive erythrocytosis (hemoglobin [Hb] ‡19 g/dL for women and ‡21 g/dL for men). Genes encoding for per- oxisome proliferator-activated receptor (PPAR) subunits a and c have been proposed as candidate genes for HA adaptation. N-acylethanolamides (NAEs) are endogenous fatty acid substances that bind to PPAR-a and -c. NAEs are also able to modulate the endocannabinoid system, a signaling pathway activated in physiological stressful conditions. In the frame of a metabolomic study, we measured plasma levels of four NAEs: palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoyl ethanolamide (SEA), and linoleoyl ethanolamide (LEA) in natives from Puno (3830 m), a city located in the Peruvian Southern Andes, and Lima (150 m). All NAEs were significantly higher in the HA population ( p < 0.001, q < 0.001). Subjects with higher NAE values were those with higher Hb concentration and lower pulse oxygen saturation. However, there was no association between NAEs and CMS score. Our results suggest that PEA and OEA could be involved in physiological regulation following long-term HA exposure. Keywords: chronic mountain sickness; hemoglobin; high altitude; hypoxemia; N-acylethanolamides Introduction H igh-altitude (HA) hypoxia is a condition of environ- mental stress (Jefferson et al., 2004) caused by decreased oxygen availability that over 200 million people worldwide have to endure (Gonzales, 2013). Failing to adapt to such environment elicits a unique disease known as chronic mountain sickness (CMS) or Monge’s disease, recognizing the first description of CMS in 1925 by Peruvian Scientist Carlos Monge. CMS is characterized by abnormally high hemoglobin (Hb) values known as excessive erythrocytosis (EE), hypoxemia, and some- times, pulmonary hypertension (Leo ´n-Velarde et al., 2005). This disease is strongly associated with inflammation and oxidative stress (Jefferson et al., 2004; Bailey et al., 2013; Julian et al., 2013). It is suggested that chronic diseases such as CMS develop after a sequence of inflammatory signals starting with an alteration in the oxidation/antioxidation bal- ance and ending with the development of the disease. EE has been described as a preclinical form of CMS and is observed before the appearance of CMS symptoms (Vargas and Spielvogel, 2006; Julian et al., 2013). Therefore, subjects with EE may have higher expression of inflammatory markers than those living at the same altitude but without EE. Peroxisome proliferator-activated receptors (PPARs) are a family of receptors comprised by three subtypes (a, b/d, and c), which altogether control metabolic homeostasis and in- flammatory processes (Tyagi et al., 2011). The PPAR-a gene is inhibited by hypoxia inducible factor (HIF)-1 in mice subject to hypoxia (Narravula and Colgan, 2001) and a putatively advantageous haplotype of this gene is negatively correlated with Hb concentration in the Tibetan population (Simonson et al., 2010). 1 Department of Biological and Physiological Sciences, Facultad de Ciencias y Filosofı ´a, Universidad Peruana Cayetano Heredia, Lima, Peru. 2 Research Circle of Plants with Effects on Health, Universidad Peruana Cayetano Heredia, Lima, Peru. 3 Universidad Nacional del Altiplano, Puno, Peru. 4 Instituto de Investigaciones en Altura, Universidad Peruana Cayetano Heredia, Lima, Peru. HIGH ALTITUDE MEDICINE & BIOLOGY Volume 00, Number 00, 2017 ª Mary Ann Liebert, Inc. DOI: 10.1089/ham.2016.0148 1 Downloaded by 209.45.17.236 from online.liebertpub.com at 07/07/17. For personal use only.