title: Plasma kallikrein-bradykinin pathway promotes circulatory nitric oxide metabolite availability during hypoxia.
abstract: Nitric oxide (NO) is an indispensible signalling molecule under hypoxic environment for both ethnic high altitude natives as well as lowland residents at high altitude. Several studies have reported higher levels of NO and bioactive NO products for both high altitude natives as well as healthy high altitude sojourners. But the metabolic pathways regulating the formation of NO and associated metabolites during hypoxia still remain elusive. In the present study, we profiled plasma proteomes of Ladakhi natives (3520 m) and lowland residents (post 1, 4 and 7 days stay) at the same altitude. This has resulted in the identification of 208 hypoxia responsive proteins (p < 0.05) and kininogen-plasma kallikrein-bradykinin as a major pathway regulating eNOS activity during hypoxia. In corroboration, we have also observed significant higher levels of plasma biomarkers for NO production (l-citrulline, nitrite, nitrate) for Ladakhi natives as compared to both lowland individuals healthy high altitude sojourners indicating higher NO availability. Since hypoxia-induced free radicals reduce NO availability, we also measured plasma levels of 8-isoprostanes, protein carbonyls and protein oxidation products in both Ladakhi natives and high altitude sojourners. Interestingly Ladakhi natives had significant lower levels of oxidative stress in comparison to high altitude sojourners but higher than lowland controls. These results suggest that plasma kallikrein-bradykinin-eNOS pathway along with moderate oxidative stress contributes to high altitude adaptation of Ladakhi natives.
authors.affiliation: Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, 110054, India.
authors.forename: Gayatri
authors.initials: G
authors.lastname: Padhy
authors.affiliation: Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, 110054, India.
authors.forename: Anamika
authors.initials: A
authors.lastname: Gangwar
authors.affiliation: Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, 110054, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, 110054, India.
authors.forename: Gidugu
authors.initials: G
authors.lastname: Himashree
authors.affiliation: Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, 110054, India.
authors.forename: Krishan
authors.initials: K
authors.lastname: Singh
authors.affiliation: Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, 110054, India.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Bhaumik
authors.affiliation: Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, 110054, India. Electronic address: kalpanab2006@gmail.com.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Bhargava
authors.affiliation: Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, 110054, India. Electronic address: nksethy@gmail.com.
authors.forename: Niroj Kumar
authors.initials: NK
authors.lastname: Sethy
mesh_terms: D000064:Acclimatization; D000328:Adult; D000531:Altitude; D000808:Angiotensinogen / Q000378:metabolism; D001120:Arginine / Q000097:blood; D001920:Bradykinin / Q000378:metabolism*; D002956:Citrulline / Q000097:blood; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D028421:Isoprostanes / Q000097:blood; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000097:blood*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020842:Plasma Kallikrein / Q000378:metabolism*; D050050:Protein Carbonylation; D020543:Proteome / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D028421:Isoprostanes; D009566:Nitrates; D009573:Nitrites; D020543:Proteome; D000808:Angiotensinogen; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D020842:Plasma Kallikrein; D001920:Bradykinin
keywords: Bradykinin; High altitude; Hypoxia; Nitric oxide; Plasma kallikrein