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Expression-Regulation of Hif-Induced Gene and Oxidative Stress Gene in Acute Hypobaric Hypoxia

Mirza Asad Beg, Imteyaz Qamar

Abstract


Hypoxia is condition in which body or some region of the body is deprived of adequate supply of oxygen. Adaptation to hypoxia is required by animals and human in several physiological and pathological situations. Hypobaric hypoxia is a pathophysiological condition which triggers redox status disturbances of cell organization leading, via an oxidative stress, to proteins, lipids and DNA damage. Identifying the molecular variables playing key roles in this process would be of paramount importance to shed light on the mechanisms known to counteract the negative effects of oxygen lack. To obtain a molecular signature, I will check the expression of the regulation of HIF induced gene and oxidative stress gene in hypobaric hypoxia, because HIF1 alpha is present in rat kept under normoxic conditions and is further increased in response to hypobaric hypoxia. Hypoxia response elements containing HIF-1 binding sites were identified in genes encoding transferrin, inducible nitric oxide synthase (iNOS), and several glycolytic enzymes, all playing important roles in systemic tissues, or intercellular O2 homeostasis allowing for increased anaerobic ATP synthesis. Adaptation to hypoxia is regulated by hypoxia inducible factor 1 (HIF1). Although HIF1 is regulated mainly by oxygen regulated tension through the oxygen-dependent degradation of its alpha-subunit. By comparing the expression of genes in hypoxic rats, the rats which are treated by a drug and with those of a normal control group, several genes with significant expressions were found. The up-regulated genes were identified as NOS2, HSP70, EpoVar-X1, SLC2A1, HIF1. These results were further validated by PCR analysis.

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Archer SL, Mike D, Crow J, Long W, Weir EK. A placebo-controlled trial of prostacyclin in acute respiratory failure in COPD, Chest. 1996; 109: 750–5p.

Asikainen TM, Ahmad A, Schneider BK, Ho WB, Arend M, Brenner M, Gunzler V, White CW (2005) Stimulation of HIF-1alpha, HIF-2alpha, and VEGF by prolyl 4-hydroxylase inhibition in human lung endothelial and epithelial cells, Free Radic Biol Med. 2005; 8: 1002–13p.

Asikainen TM, Chang LY, Coalson JJ, Schneider BK, Waleh NS Ikegami M, Shannon JM, Winter VT, Grubb P, Clyman RI, Yoder BA, Crapo JD, White CW (2006) Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity, FASEB J. 2006; 10: 1698–700p.

Barst RJ, McGoon M, McLaughlin V, Tapson V, Rich S, Rubin L, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003; 41: 2119–25p.

Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The primary pulmonary hypertension study group, N Engl J Med. 1996; 334: 296–302p.

Bradly G. Wouters, Marianne Koritzinsky* Hypoxia signalling through mTOR and the unfolded protein response in cancer, Nat Rev.

Bray F, Moller B. Predicting the future burden of cancer, Nat Rev Cancer. 2006; 6: 63–74p.

Bresser P, Fedullo PF, Auger WR, Channick RN, Robbins IM, Kerr KM, et al. Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension, Eur Respir J. 2004; 23: 595–600p.

Carmeliet P, Dor Y, Herbert JM, FukumuraD, Brusselmans K, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis, Nature. 1998; 394: 485–90p.

Cavill I Erythropoiesis and iron, Best Pract Res Clin Haematol. 2002; 15: 399–409p.

Chandel NS, Budinger GR, Schumacker PT (1996) Molecular oxygen modulates cytochrome c oxidase function. J Biol Chem. 1996; 271: 18672–7p.

Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 2009; 37: W305–11p.

Clapp LH, Finney P, Turcato S, Tran S, Rubin LJ, Tinker A. Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery, Am J Respir Cell Mol Biol. 2002; 26: 194–201p.

Colditz GA, Sellers TA, Trapido E (2006) Epidemiology—identifying the causes and preventability of cancer? Nat Rev Cancer. 2006; 6: 75–83p.

Easley RB, Fuld MK, Fernandez-Bustamante A, Hoffman EA, Simon BA (2006) Mechanism of hypoxemia in acute lung injury evaluated by multidetector-row CT, Acad Radiol. 2006; 7: 916–21p.

Finkel T, Serrano M, BlascoMA (2007) The common biology of cancer and ageing, Nature. 2007; 448: 767–74p.

Folkman J, Hahnfeldt P, Hlatky L (2000) Cancer: looking outside the genome, Nat Rev Mol Cell Biol. 2000; 1: 76–9p.

Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, et al. (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996; 16: 4604–13p.

Frisancho AR (1975) Functional adaptation to high altitude hypoxia. Science. 1975; 187: 313–9p.

Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, doubleblind, placebo-controlled trial. J Am Coll Cardiol. 2002; 39: 1496–502p.

Ghofrani HA, Voswinckel R, Reichenberger F, Weissmann N, Schermuly RT, Seeger W, Grimminger F (2006) Hypoxia- and non-hypoxia-related pulmonary hypertension—established and new therapies. Cardiovasc Res. 2006; 1: 30–40p.

Gomme PT, Bertolini J (2004) Therapeutic potential of vitamin D-binding protein. Trends Biotechnol. 2004; 22: 340–5p.

Groenman FA, Rutter M, Wang J, Caniggia I, Tibboel D, Post M. Effect of chemical stabilizers of hypoxia-inducible factorson early lung development. Am J Physiol Lung Cell MolPhysiol. 2007; 3: L557–67p.

Handelman GJ, Levin NW (2008) Iron and anemia in human biology: a review of mechanisms. Heart Fail Rev. 13: 393–404p.

Hewett-Emmet, D.In: W. R. Chegwidden, Y. Edwards, and N. Carter (eds.), The Carbonic Anhydrases: New Horizons. Boston: Birkhauser; 2000.

Hoeper MM, Olschewski H, GhofraniHA, Wilkens H, Winkler J, BorstMM, et al. A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group, J Am Coll Cardiol. 2000; 35: 176–82p.

Hoffman EA, Simon BA, McLennan G (2006) State of the art. A structural and functional assessment of the lung via multidetector row computed tomography: phenotyping chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006; 6: 519–32p.

Jessen TH, Weber RE, Fermi G, Tame J, Braunitzer G (1991) Adaptation of bird hemoglobins to high altitudes: demonstration of molecular mechanism by protein engineering, Proc Natl Acad Sci U S A. 1991; 88: 6519–22p.

Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem. 1996; 271: 17771–8p.

Liao, S. Y., Aurelio, O. N., Zavada, J., and Stanbridge, E. J. Identification of MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res. 1997; 57: 2828–31p.

Liao, S. Y., Brewer, C., Zavada, J., Pastorek, J., Pastorekova, S., Manetta, A., Berman, M. L., DiSaia, P. J., and Stanbridge, E. J. Identification of the MN antigen as a diagnostic biomarker of cervical intraepithelial squamous and glandular neoplasiaand cervical carcinomas, Am J Pathol. 1994; 145: 598–609p.

Lind SE, Smith DB, Janmey PA, Stossel TP (1988) Depression of gelsolinlevelsanddetection of gelsolin-actin complexes in plasma of patients with acute lunginjury, Am Rev Respir Dis. 1988; 138: 429–43p.

Lok CN, Ponka P (1999) Identification of a hypoxia response element in the transferrin receptor gene, J Biol Chem. 1999; 274: 24147–52p.

Mairbaurl H (1994) Red blood cell function in hypoxia at altitude and exercise. Int J Sports Med. 1994; 15: 51–63p.

Melo MB, Bordin S, Duarte AS, Ogo SH, Torsoni MA, et al. (2003) Molecular characterization of hemoglobin alpha-D chains from Geochelonecarbonariaand Geochelonedenticulata land turtles, Comp Biochem Physiol B Biochem Mol Biol. 2003; 134: 389–95p.

Minamino T, Christou H, Hsieh CM, Li Y, Dhawan V, Abraham NJ, Perrella MA, Mitsialis SA, Kourembanas S (2001) Targeted expression of hemeoxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci USA. 2001; 15: 8798–803p.

Moehler TM, Ho AD, Goldschmidt H, Barlogie B Angiogenesis in hematologic malignancies, Crit Rev OncolHematol. 2003; 45: 227–44p.

Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976; 263: 663–5p.

Moncada S, Higgs EA. Prostaglandins in the pathogenesis and prevention of vascular disease. Blood Rev. 1987; 1: 141–5p.

N Yukawa, N Carter, G Rutty, M A Green Intra-alveolar haemorrhage in sudden infant death syndrome: a cause for concern, J Clin Pathol. 1999; 52: 581–7p.

Pastorek, J., Pastorekova, S., Callebaut, I., Mornon, J. P., Zelnik, V., Opavsky, R.,Zat’ovicova, M., Liao, S., Portetelle, D., Stanbridge, E. J.,et al. Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene. 1994; 9: 2877–88p.

Rolfs A, Kvietikova I, Gassmann M, Wenger RH (1997) Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J BiolChem. 1997; 272: 20055–62p.

Saarnio, J. S. P., Parkkila, A-K., Haukipuro, K.,Pastorekova, S., Pastorek, J.,Kairaluoma, M., and Karttunen, T. J. Immunohistochemical study of colorectal tumors for expression of novel transmembrane carbonic anhydrase. MN/CA IX, with potential value as a marker of cell proliferation. Am. J. Pathol. 1998; 153: 279–85p.

Schumacker PT, Chandel N, Agusti AG. Oxygen conformance of cellular respiration in hepatocytes. Am J Physiol 1993; 265: L395–402p.

Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, et al.Continuous subcutaneous infusion of treprostinil, a prostacyclinanalogue, in patients with pulmonary arterial hypertension: a doubleblind, randomized, placebo-controlled trial. Am J RespirCrit Care Med. 2002; 165: 800–4p.

Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, etal.Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005; 111: 3105–11p.

Sly, W. S., and Hu, P. Y. Human carbonic anhydrases and carbonic anhydrase deficiencies. Annu. Rev. Biochem. 1995; 64: 375–401p.

Storey KB (1996) Metabolic adaptations supporting anoxia tolerance in reptiles:recentadvances. Comp BiochemPhysiol B BiochemMolBiol. 1996; 113: 23–35p.

Storz JF, Runck AM, Sabatino SJ, Kelly JK, Ferrand N, et al. (2009) Evolutionary and functional insights into the mechanism underlying highaltitude adaptation of deer mouse hemoglobin, ProcNatlAcadSci U S A. 2009; 106: 14450–5p.

Subramanian RM, Chandel N, Budinger GR, Schumacker PT (2007) Hypoxic conformance of metabolism in primary rat hepatocytes: a model of hepatic hibernation. Hepatology. 2007; 45: 455–64p.

Swenson ER (2006) Hypoxic lung whiteout: further clearing but more questions from on high. Ann Intern Med. 7: 550–2p.

Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G (1999) Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cellspecific post-transcriptional regulation. J BiolChem. 1999; 274: 24142–6p.

Timothyd. Lecras, Chun Xue, Appavoo Rengasamy, and Roger A. Johns Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung Department of Anesthesiology, University of Virginia, Charlottesville, Virginia 22908

Vermylen, P., Roufosse, C., Burny, A., Bosschaerts, T., Pastorekova, S., Ninane, V., and Sculier, J. P. Carbonic anhydrase IX antigen differentiates between pre-neoplastic and malignant lesions in non-small cell lung carcinoma, Eur. Respir. J. 1999; 14: 806–11p.

Voelkel NF, Tuder RM (2000) Hypoxia-induced pulmonary vascular remodeling—a model for what human disease. J ClinInvest. 2000; 6: 733–8p.

von Euler US, Liljsjestrand G (1946) Observations of the pulmonary arterial blood pressure on the cat, Acta Physiol Scand. 1946; 12: 301–20p.

Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. ProcNatlAcadSci U S A. 92: 5510–4p.

Weissmann N, Sommer N, Schermuly RT, Ghofrani HA, Seeger W, Grimminger F (2006) Oxygen sensors in hypoxic pulmonary vasoconstriction. Cardiovasc Res. 2006; 4: 620–9p.

William R. Wilson and Michael P. Hay Targeting hypoxia in cancer therapy Nat Rev.

Wykoff, C. C., Beasley, N. J. P., Watson, P. H., Turner, K. J., Pastorek, J., Sibtain, A.,Wilson, G. D., Turley, H., Talks, K. L., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J.,and Harris, A. L. Hypoxia-inducible expression of tumor-associated carbonic anhydrases, Cancer Res. 2000; 60: 7075–83p.

Yamamoto N, Homma S, Haddad JG, Kowalski MA (1991) Vitamin D3 binding protein required for in vitro activation of macrophages after alkylglycerol treatment of mouse peritoneal cells. Immunology. 1991; 74: 420–4p.

J. Zavada, Z. Zavadova, S. Pastorekova, F. Ciampor, J. Pastorek, V. Zelnik. Expression of MaTu-MN protein in human tumor cultures and in clinical specimens, Int J Cancer. 1993; 54: 268–74p.


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