ABSTRACT
Plasma proteomics of Ladakhi natives reveal functional regulation between renin–angiotensin system and eNOS–cGMP pathway. High Alt Med Biol. 16:000–000, 2016.—Humans have been living in high altitudes for more than 25,000 years but the molecular pathways promoting survival and performance in these extreme environments are not well elucidated. In an attempt to understand human adaptation to high altitudes, we used two-dimensional gel electrophoresis combined with MALDI-TOF/TOF to identify plasma proteins and associated pathways of ethnic Ladakhi natives residing at 3520 m. This resulted in the identification of 36 differential proteins compared with sea-level individuals. Proteins belonging to coagulation cascade and complement activation were found to be less abundant in Ladakhi natives. Interestingly, we observed lower abundance of angiotensinogen (ANGT) and subsequent analysis also revealed lower levels of both ANGT and angiotensin II (Ang II) in Ladakhi natives. Concomitantly, we observed elevated levels of eNOS, phosphorylated eNOS (Ser1177), and plasma biomarkers for nitric oxide (NO) production (nitrate and nitrite) and availability (cGMP). These results suggest that functional interplay between renin–angiotensin system and NO–cGMP pathway contributes to the hypoxia adaptation in Ladakhi natives. These findings will augment the present understanding of higher NO and NO-derived metabolite availability during human adaptation to high altitude.