title: S1P prophylaxis mitigates acute hypobaric hypoxia-induced molecular, biochemical, and metabolic disturbances: A preclinical report.
abstract: Sphingosine-1-phosphate (S1P) is emerging to have hypoxic preconditioning potential in various preclinical studies. The study aims to evaluate the preclinical preconditioning efficacy of exogenously administered S1P against acute hypobaric hypoxia (HH)-induced pathological disturbances. Male Sprague Dawley rats (200 ± 20 g) were preconditioned with 1, 10, and 100 μg/kg body weight (b.w.) S1P (i.v.) for three consecutive days. On the third day, S1P preconditioned animals, along with hypoxia control animals, were exposed to HH equivalent to 7,620 m (280 mm Hg) for 6 h. Postexposure status of cardiac energy production, circulatory vasoactive mediators, pulmonary and cerebral oxidative damage, and inflammation were assessed. HH exposure led to cardiac energy deficit indicated by low ATP levels and pronounced AMPK activation levels, raised circulatory levels of brain natriuretic peptide and endothelin-1 with respect to total nitrate (NOx), redox imbalance, inflammation, and alterations in NOx levels in the pulmonary and cerebral tissues. These pathological precursors have been routinely reported to be coincident with high-altitude diseases. Preconditioning with S1P, especially 1 µg/kg b.w. dose, was seen to reverse the manifestation of these pathological disturbances. The protective efficacy could be attributed, at least in part, to enhanced activity of cardioprotective protein kinase C and activation of small GTPase Rac1, which led to further induction of hypoxia-adaptive molecular mediators: hypoxia-inducible factor (HIF)-1α and Hsp70. This is a first such report, to the best of our knowledge, elucidating the mechanism of exogenous S1P-mediated HIF-1α/Hsp70 induction. Conclusively, systemic preconditioning with 1 μg/kg b.w. S1P in rats protects against acute HH-induced pathological disturbances. © 2016 IUBMB Life 68(5):365-375, 2016.
authors.affiliation: Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Timarpur, New Delhi, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Chawla
authors.affiliation: Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Timarpur, New Delhi, India.
authors.forename: Babita
authors.initials: B
authors.lastname: Rahar
authors.affiliation: Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Timarpur, New Delhi, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Saxena
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D004353:Drug Evaluation, Preclinical; D019332:Endothelin-1 / Q000097:blood; D004734:Energy Metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000860:Hypoxia / Q000097:blood / Q000517:prevention & control*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008246:Lysophospholipids / Q000008:administration & dosage*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009569:Nitric Oxide / Q000097:blood; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D055550:Protein Stability; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D016207:Cytokines; D019332:Endothelin-1; D018840:HSP70 Heat-Shock Proteins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008246:Lysophospholipids; D020097:Natriuretic Peptide, Brain; C060506:sphingosine 1-phosphate; D009569:Nitric Oxide; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D013110:Sphingosine
keywords: AMPK; BNP; HIF-1α; Hsp70; PKC; Rac1; S1P preconditioning; hypobaric hypoxia