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. 2003 Feb 15;370(Pt 1):149–157. doi: 10.1042/BJ20021087

Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1.

Yang-Sook Chun 1, Ju-Yeon Hyun 1, Yong-Geun Kwak 1, In-San Kim 1, Chan-Hyung Kim 1, Eunjoo Choi 1, Myung-Suk Kim 1, Jong-Wan Park 1
PMCID: PMC1223144  PMID: 12413399

Abstract

Atrial natriuretic peptide (ANP) is a cardiac peptide, the transcription of which is up-regulated in the ischaemic ventricle. However, the molecular mechanism of ANP induction is unclear. This study demonstrated that ANP mRNA expression in rat ventricular myocardium is induced in an early phase of ischaemia, preceded by hypoxia-inducible factor-1 (HIF-1) alpha expression. The ANP gene was also induced by hypoxia or HIF-1 inducers such as CoCl2 and desferrioxamine in H9c2 and neonatal cardiomyocytes. The 2307 bp 5'-flanking region of the rat ANP gene was cloned and fused to the luciferase gene. Evidence of the promoter activity was only apparent in the myocytes and was induced by hypoxia and HIF-1 inducers. The overexpression of HIF-1alpha markedly enhanced ANP promoter activity, and a dominant-negative isoform completely suppressed it. We demonstrated that the promoter regions are essential for hypoxic ANP induction. One promoter region, containing the HIF-1-binding sequence, is regulated directly by HIF-1. The other region is also activated by HIF-1 despite having no HIF-1-binding sequence. These results suggest that HIF-1 enhances the transactivation of the ANP gene in hypoxic myocytes, implying that stimulation of the ANP promoter by HIF-1 may in fact be responsible for the induction of the ANP gene in ischaemic ventricular myocardium.

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Selected References

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  1. Brenner B. M., Ballermann B. J., Gunning M. E., Zeidel M. L. Diverse biological actions of atrial natriuretic peptide. Physiol Rev. 1990 Jul;70(3):665–699. doi: 10.1152/physrev.1990.70.3.665. [DOI] [PubMed] [Google Scholar]
  2. Chen Y. F., Durand J., Claycomb W. C. Hypoxia stimulates atrial natriuretic peptide gene expression in cultured atrial cardiocytes. Hypertension. 1997 Jan;29(1 Pt 1):75–82. doi: 10.1161/01.hyp.29.1.75. [DOI] [PubMed] [Google Scholar]
  3. Chun Y. S., Choi E., Kim G. T., Choi H., Kim C. H., Lee M. J., Kim M. S., Park J. W. Cadmium blocks hypoxia-inducible factor (HIF)-1-mediated response to hypoxia by stimulating the proteasome-dependent degradation of HIF-1alpha. Eur J Biochem. 2000 Jul;267(13):4198–4204. doi: 10.1046/j.1432-1327.2000.01453.x. [DOI] [PubMed] [Google Scholar]
  4. Chun Y. S., Choi E., Kim G. T., Lee M. J., Lee M. J., Lee S. E., Kim M. S., Park J. W. Zinc induces the accumulation of hypoxia-inducible factor (HIF)-1alpha, but inhibits the nuclear translocation of HIF-1beta, causing HIF-1 inactivation. Biochem Biophys Res Commun. 2000 Feb 16;268(2):652–656. doi: 10.1006/bbrc.2000.2180. [DOI] [PubMed] [Google Scholar]
  5. Chun Yang-Sook, Choi Eunjoo, Kim Tae-You, Kim Myung-Suk, Park Jong-Wan. A dominant-negative isoform lacking exons 11 and 12 of the human hypoxia-inducible factor-1alpha gene. Biochem J. 2002 Feb 15;362(Pt 1):71–79. doi: 10.1042/0264-6021:3620071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Drexler H., Hänze J., Finckh M., Lu W., Just H., Lang R. E. Atrial natriuretic peptide in a rat model of cardiac failure. Atrial and ventricular mRNA, atrial content, plasma levels, and effect of volume loading. Circulation. 1989 Mar;79(3):620–633. doi: 10.1161/01.cir.79.3.620. [DOI] [PubMed] [Google Scholar]
  7. Drexler H., Hänze J., Finckh M., Lu W., Just H., Lang R. E. Atrial natriuretic peptide in a rat model of cardiac failure. Atrial and ventricular mRNA, atrial content, plasma levels, and effect of volume loading. Circulation. 1989 Mar;79(3):620–633. doi: 10.1161/01.cir.79.3.620. [DOI] [PubMed] [Google Scholar]
  8. Forsythe J. A., Jiang B. H., Iyer N. V., Agani F., Leung S. W., Koos R. D., Semenza G. L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996 Sep;16(9):4604–4613. doi: 10.1128/mcb.16.9.4604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fyhrquist F., Sirviö M. L., Helin K., Saijonmaa O., Metsärinne K., Paakkari I., Järvinen A., Tikkanen I. Endothelin antiserum decreases volume-stimulated and basal plasma concentration of atrial natriuretic peptide. Circulation. 1993 Sep;88(3):1172–1176. doi: 10.1161/01.cir.88.3.1172. [DOI] [PubMed] [Google Scholar]
  10. Garayoa M., Martínez A., Lee S., Pío R., An W. G., Neckers L., Trepel J., Montuenga L. M., Ryan H., Johnson R. Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis. Mol Endocrinol. 2000 Jun;14(6):848–862. doi: 10.1210/mend.14.6.0473. [DOI] [PubMed] [Google Scholar]
  11. Hu J., Discher D. J., Bishopric N. H., Webster K. A. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Commun. 1998 Apr 28;245(3):894–899. doi: 10.1006/bbrc.1998.8543. [DOI] [PubMed] [Google Scholar]
  12. Ivan M., Kondo K., Yang H., Kim W., Valiando J., Ohh M., Salic A., Asara J. M., Lane W. S., Kaelin W. G., Jr HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001 Apr 5;292(5516):464–468. doi: 10.1126/science.1059817. [DOI] [PubMed] [Google Scholar]
  13. Jaakkola P., Mole D. R., Tian Y. M., Wilson M. I., Gielbert J., Gaskell S. J., von Kriegsheim A., Hebestreit H. F., Mukherji M., Schofield C. J. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001 Apr 5;292(5516):468–472. doi: 10.1126/science.1059796. [DOI] [PubMed] [Google Scholar]
  14. Jung F., Palmer L. A., Zhou N., Johns R. A. Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes. Circ Res. 2000 Feb 18;86(3):319–325. doi: 10.1161/01.res.86.3.319. [DOI] [PubMed] [Google Scholar]
  15. Kim Chan-Hyung, Cho Young-Suk, Chun Yang-Sook, Park Jong-Wan, Kim Myung-Suk. Early expression of myocardial HIF-1alpha in response to mechanical stresses: regulation by stretch-activated channels and the phosphatidylinositol 3-kinase signaling pathway. Circ Res. 2002 Feb 8;90(2):E25–E33. doi: 10.1161/hh0202.104923. [DOI] [PubMed] [Google Scholar]
  16. Kimes B. W., Brandt B. L. Properties of a clonal muscle cell line from rat heart. Exp Cell Res. 1976 Mar 15;98(2):367–381. doi: 10.1016/0014-4827(76)90447-x. [DOI] [PubMed] [Google Scholar]
  17. Kline R. P., Sorota S., Dresdner K. P., Steinhelper M. E., Lanson N. A., Jr, Wit A. L., Claycomb W. C., Field L. J. Spontaneous activity in transgenic mouse heart: comparison of primary atrial tumor with cultured AT-1 atrial myocytes. J Cardiovasc Electrophysiol. 1993 Dec;4(6):642–660. doi: 10.1111/j.1540-8167.1993.tb01251.x. [DOI] [PubMed] [Google Scholar]
  18. Lee P. J., Jiang B. H., Chin B. Y., Iyer N. V., Alam J., Semenza G. L., Choi A. M. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem. 1997 Feb 28;272(9):5375–5381. [PubMed] [Google Scholar]
  19. Lee S. H., Wolf P. L., Escudero R., Deutsch R., Jamieson S. W., Thistlethwaite P. A. Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med. 2000 Mar 2;342(9):626–633. doi: 10.1056/NEJM200003023420904. [DOI] [PubMed] [Google Scholar]
  20. Loennechen J. P., Støylen A., Beisvag V., Wisløff U., Ellingsen O. Regional expression of endothelin-1, ANP, IGF-1, and LV wall stress in the infarcted rat heart. Am J Physiol Heart Circ Physiol. 2001 Jun;280(6):H2902–H2910. doi: 10.1152/ajpheart.2001.280.6.H2902. [DOI] [PubMed] [Google Scholar]
  21. Masson N., Willam C., Maxwell P. H., Pugh C. W., Ratcliffe P. J. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 2001 Sep 17;20(18):5197–5206. doi: 10.1093/emboj/20.18.5197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Maxwell P. H., Wiesener M. S., Chang G. W., Clifford S. C., Vaux E. C., Cockman M. E., Wykoff C. C., Pugh C. W., Maher E. R., Ratcliffe P. J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999 May 20;399(6733):271–275. doi: 10.1038/20459. [DOI] [PubMed] [Google Scholar]
  23. Semenza G. L. HIF-1 and human disease: one highly involved factor. Genes Dev. 2000 Aug 15;14(16):1983–1991. [PubMed] [Google Scholar]
  24. Simpson D. G., Terracio L., Terracio M., Price R. L., Turner D. C., Borg T. K. Modulation of cardiac myocyte phenotype in vitro by the composition and orientation of the extracellular matrix. J Cell Physiol. 1994 Oct;161(1):89–105. doi: 10.1002/jcp.1041610112. [DOI] [PubMed] [Google Scholar]
  25. Wang G. L., Semenza G. L. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995 Jan 20;270(3):1230–1237. doi: 10.1074/jbc.270.3.1230. [DOI] [PubMed] [Google Scholar]
  26. Wu J. P., Kovacic-Milivojević B., Lapointe M. C., Nakamura K., Gardner D. G. Cis-active determinants of cardiac-specific expression in the human atrial natriuretic peptide gene. Mol Endocrinol. 1991 Sep;5(9):1311–1322. doi: 10.1210/mend-5-9-1311. [DOI] [PubMed] [Google Scholar]
  27. de Bold A. J. Atrial natriuretic factor: a hormone produced by the heart. Science. 1985 Nov 15;230(4727):767–770. doi: 10.1126/science.2932797. [DOI] [PubMed] [Google Scholar]

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