Adrenomedullin has effects on hypoxia-inducible factor 1-alpha in hypoxia in several organs of female rats

Öz

Objective: Vascular dysfunction induces impaired O2 delivery and hypoxia, and adrenomedullin (AdM) have a role in hypoxia and angiogenesis. The reaction of the organism exposed to hypoxia and the effect of AdM over HIF-1α has been investigated in this study. Material and Methods: Female rats were divided into 4 groups (control, hypoxia, control + AdM and hypoxia + AdM). Hypoxia groups were provided hypoxia containing 10% oxygen and 90% nitrogen for 1 week. AdM treatment groups were injected 1.25 nmol/kg AdM for 4 days intraperitoneally. AdM and HIF-1α levels were measured in heart, lung, and kidney tissues with ELISA. Results: AdM levels increased in hypoxia + AdM group than hypoxia group, however, was not increased in control + AdM group when compared with the control group in heart tissue. Contrarily, AdM decreased in control + AdM group in the kidney, while increased in control + AdM, and hypoxia + AdM groups in the lung when compared to the control group. The HIF-1α level was higher in control + AdM group in the kidney, and hypoxia + AdM group in the lung. HIF-1α levels in heart tissue were decreased in hypoxia group when compared to the control group. Conclusion: Tissues respond to hypoxic conditions at different times, and at distinct levels. AdM may be used to induce HIF-1α therapeutically before ischemic conditions.

Anahtar Kelimeler

• Adrenomedullin,hypoxia,hypoxia-inducible factor 1α,angiogenesis

Kaynakça

1. 1. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia HIF system. Nat Med 2003;9(6):677–84.
2. 2. Costa C, Soares R, Schmitt F. Angiogenesis: now and then. APMIS 2004;112(7–8):402–12.
3. 3. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992;12(12):5447–54.
4. 4. Jelkmann W. Erythropoietin: structure, control of production, and function. Physiol Rev 1992;72(2):449–89.
5. 5. Wenger RH. Cellular adaptation to hypoxia: O2 -sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2 -regulated gene expression. FASEB J 2002;16(10):1151–62.
6. 6. Wiesener MS, Turley H, Allen WE, Willam C, Eckardt KU, Talks KL, et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha. Blood. 1998;92(7):2260–8.
7. 7. Kim S, Kim J, Lee S, Park J. Adrenomedullin protects against hypoxia / reoxygenation-induced cell death by suppression of reactive oxygen species via thiol redox systems. FEBS Lett 2010;584(1):213–8.
8. 8. Kitamura K, Kangawa K, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993;192:553–60.

9. 9. Larráyoz IM, Martínez-herrero S, García-sanmartín J, Ochoa-callejero L, Martínez A. Adrenomedullin and tumour microenvironment. J Transl Med 2014;12(339):1–15.
10. 10. Park SC, Yoon J-H, Lee J-H, Yu SJ, Myung SJ, Kim W, et al. Hypoxia-inducible adrenomedullin accelerates hepatocellular carcinoma cell growth. Cancer Lett 2008;271(2):314–22.
11. 11. Hinson JP, Kapas S, Smith DM. Adrenomedullin, a Multifunctional Regulatory Peptide. Endocr Rev. 2000;21(2):138–67.
12. 12. Karpinich NO, Hoopes SL, Kechele DO, Lenhart PM, Caron KM. Adrenomedullin Function in Vascular Endothelial Cells: Insights from Genetic Mouse Models. Curr Hypertens Rev 2011;7(4):228–39.
13. 13. Meyrick B, Miller J, Reid L. Pulmonary oedema induced by antu, or by high or low oxygen concentrations in rat - an electron microscopic study. Bri J exp Path 1972;53(4):347–58.
14. 14. Chunyu Z, Junbao D, Dingfang B, Hui Y, Xiuying T, Chaoshu T. The regulatory effect of hydrogen sulfide on hypoxic pulmonary hypertension in rats. Biochem Biophys Res Commun 2003;302(4):810–6.
15. 15. Rosenberger C, Mandriota S, Jürgensen JS, Wiesener MS, Hörstrup JH, Frei U, et al. Expression of hypoxia-inducible factor-1 alpha and -2 alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol 2002;13(7):1721–32.
16. 16. Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DAH, Bauer C, et al. HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. FASEB J 2001;15:2445–53.
17. 17. Wiesener MS, Jürgensen JS, Rosenberger C, Scholze C, Hörstrup JH, Warnecke C, et al. Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J 2003;17(1):271–3.
18. 18. Carreau A, Hafny-rahbi B El, Matejuk A, Grillon C, Kieda C. Why is the partial oxygen pressure of human tissues a crucial parameter ? Small molecules and hypoxia Imaging of hypoxic areas. J Cell Mol Med 2011;15(6):1239–53.
19. 19. Krock BL, Skuli N, Simon MC. Hypoxia-Induced Angiogenesis : Good and Evil. Genes Cancer 2011;2(12):1117–33.
20. 20. Jin KL, Mao XO, Nagayama T, Goldsmith PC, Greenberg DA. Induction of vascular endothelial growth factor and hypoxia-inducible factor-1alpha by global ischemia in rat brain. Neuroscience 2000;99(3):577–85.
21. 21. Oehler MK, Fischer DC, Orlowska-Volk M, Herrle F, Kieback DG, Rees MCP, et al. Tissue and plasma expression of the angiogenic peptide adrenomedullin in breast cancer. Br J Cancer 2003;89:1927–33.
22. 22. Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol 2015;402:113–9.
23. 23. Looi YH, Kane KA, McPhaden AR, Wainwright CL. Adrenomedullin acts via nitric oxide and peroxynitrite to protect against myocardial ischaemia-induced arrhythmias in anaesthetized rats. Br J Pharmacol 2006;148:599–609.
24. 24. Cameron VA, Fleming AM. Novel Sites of Adrenomedullin Gene Expression in Mouse and Rat Tissues. Endocrinology 1998;139(5):2253–64.