Chawla Sonam, Rahar Babita, Saxena Shweta
Experimental Biology Division, Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Timarpur, New Delhi, India.
IUBMB Life. 2016 May;68(5):365-75. doi: 10.1002/iub.1489. Epub 2016 Mar 9.
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.
在各种临床前研究中，1-磷酸鞘氨醇（S1P）正显示出具有低氧预处理潜力。本研究旨在评估外源性给予S1P对急性低压缺氧（HH）诱导的病理紊乱的临床前预处理效果。雄性Sprague Dawley大鼠（200±20 g）连续三天分别用1、10和100 μg/kg体重（b.w.）的S1P（静脉注射）进行预处理。在第三天，将经S1P预处理的动物与缺氧对照动物一起暴露于相当于海拔7620米（280毫米汞柱）的HH环境中6小时。评估暴露后心脏能量产生、循环血管活性介质、肺和脑氧化损伤以及炎症的状态。HH暴露导致心脏能量缺乏，表现为ATP水平降低和明显的AMPK激活水平升高，相对于总硝酸盐（NOx），循环中脑钠肽和内皮素-1水平升高，氧化还原失衡、炎症以及肺和脑组织中NOx水平改变。这些病理先兆通常被报道与高原疾病同时出现。用S1P预处理，尤其是1 μg/kg b.w.剂量，可逆转这些病理紊乱的表现。这种保护作用至少部分可归因于心脏保护蛋白激酶C活性增强和小GTP酶Rac1激活，这导致进一步诱导缺氧适应性分子介质：缺氧诱导因子（HIF）-1α和热休克蛋白70（Hsp70）。据我们所知，这是第一份阐明外源性S1P介导的HIF-1α/Hsp70诱导机制的此类报告。总之，大鼠全身性给予1 μg/kg b.w.的S1P预处理可预防急性HH诱导的病理紊乱。© 2016国际生物化学与分子生物学联盟生命科学68(5):365 - 375, 2016。
