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Endothelin-converting enzyme in human tissues

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Abstract

Our aim was to determine whether the expression of endothelin-converting enzyme in human tissues would correlate with the distribution of its substrate, big endothelin-1, and its product, the mature peptide. Site-directed antisera raised against the conserved C-terminus of the mammalian enzyme were used to measure the immunoreactive enzyme in microsomal fractions prepared from tissue homogenates and to localize staining to the endothelial cells lining large conduit and smaller resistance vessels within cardiac, adrenal, respiratory and brain tissue. The activity of endothelin-converting enzyme was measured and characterized in isolated endothelial cells. This pattern of staining in the vascular endothelium paralleled that of mature endothelin and big endothelin-1, and these peptides were detectable by radioimmunoassay in all tissues examined. Immunoreactive endothelin-converting enzyme localized to other cell types, including bronchial epithelial cells, and to fibres within the glial limitans, neuronal processes and cell bodies of the cerebral cortex. Although perivascular astrocytes in the subcortical white matter displayed intense endothelin-converting enzyme-like immunoreactivity, endothelin staining was not detected. The results suggest that endothelin-converting enzyme has a ubiquitous distribution within the human vascular endothelium and is positioned to catalyse the conversion of big endothelin-1 to the biologically active endothelin-1, which on release may contribute to the maintenance of basal tone in humans. Endothelin-converting enzyme localized to epithelial cells in peripheral tissues or astrocytes within the brain may be upregulated in pathophysiological conditions in which endothelin levels are increased and could represent a further target for therapeutic intervention by enzyme inhibitors. © 1998 Chapman & Hall

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References

  • Advenier, C, Lagente, V, Zhang, Y. & Naline, E. (1992) Contractile activity of big endothelin-1 on the human isolated bronchus. Br. J. Pharmacol. 106, 883-7.

    PubMed  Google Scholar 

  • ashby, M. J., Plumpton, C., Teale, P., Kuc, R.E., Houghton, E. & Davenport, A.P. (1995) Analysis of endogenous human endothelin peptides by high-performance liquid chromatography and mass spectrometry. J. Cardiovasc. Pharmacol. 26 (suppl. 3), S247-9.

    PubMed  Google Scholar 

  • Bacon, C.R., Cary, N.R. & Davenport, A.P. (1995) Distribution of endothelin receptors in atherosclerotic human coronary arteries. J. Cardiovasc. Pharmacol. 26 (Suppl. 3), S439-41.

    PubMed  Google Scholar 

  • Barnes, K., Shimada, K., Takahashi, M., Tanzawa, K. & Turner, A. J. (1996) Metallopeptidase inhibitors induce an up-regulation of endothelin-converting enzyme levels and its redistribution from the plasma membrane to an intracellular compartment. J. Cell Sci. 109, 919-28.

    PubMed  Google Scholar 

  • Barnes, K., Walkden, B. J., Wilkinson, T.C. & Turner, A.J. (1997) Expression of endothelin-converting enzyme in both neuroblastoma and glial cells and its localization in rat hippocampus. J. Neurochem. 68, 570-7.

    PubMed  Google Scholar 

  • Barone, F.C., Willette, R.N., Yue, T.L. & Feurestein, G. (1995) Therapeutic effects of endothelin receptor antagonists in stroke. Neurol. Res. 17, 259-64.

    PubMed  Google Scholar 

  • Bax, W.A., Aghai, Z., Van Tricht, C.L., Wassenaar, C. & Saxena, P.R. (1994) Different endothelin receptors involved in endothelin-1-and sarafotoxin S6B-induced contractions of the human isolated coronary artery. Br. J. Pharmacol. 113, 1471-9.

    PubMed  Google Scholar 

  • Cameron, I.T., Davenport, A.P., Van Papendorp, C., Barker, P. J., Huskisson, N.S., Gilmour, R.S., Brown, M. J. & Smith, S.K. (1992) Endothelin-like immunoreactivity in human endometrium. J. Reprod. Fertil. 95, 623-8.

    PubMed  Google Scholar 

  • Davenport, A.P., Nunez, D.J., Hall, J.A., Kaumann, A.J. & Brown, M. J. (1989) Autoradiographical localization of binding sites for porcine [125I] endothelin-1 in humans, pigs, and rats: functional relevance in humans. J. Cardiovasc. Pharmacol. 13 (Suppl. 5), S166-70.

    PubMed  Google Scholar 

  • Davenport, A.P., Hoskins, S.L., Kuc, R.E. & Plumpton, C. (1996) Differential distribution of endothelin peptides and receptors in human adrenal gland. Histochem. J. 28, 779-89.

    PubMed  Google Scholar 

  • Dryberg, T. & Oldstone, M.B.A. (1986) Peptides as antigens. J. Exp. Med. 164, 1344-9.

    Article  PubMed  Google Scholar 

  • Emoto, N. & Yanagisawa, M. (1995) Endothelin-converting enzyme-2 is a membrane-bound, phosphoramidon-sensitive metalloprotease with acidic pH optimum. J. Biol. Chem. 270, 15262-8.

    Article  PubMed  Google Scholar 

  • Emoto, N., Xie, J. & Yanagisawa, M. (1996) Intracellular and cell-surface isoforms of endothelin-converting enzyme-1 generated by tissue-specific alternative splicing (abstract). Circulation 94, 8SS, 3433.

    Google Scholar 

  • Escrig, C., Bishop, A.E., Inagaki, H., Moscoso, G., Takahashi, K., Varndell, I.M., Ghatei, M.A., Bloom, S.R. & Polak, J.M. (1992) Localisation of endothelin like immunoreactivity in adult and developing human gut. Gut 33, 212-17.

    PubMed  Google Scholar 

  • Furukawa, K., Saleh, D., Bayan, F., Emoto, N., Kaw, S., Yanagisawa, M. & Giaid, A. (1996) Co-expression of endothelin-1 and endothelin-converting enzyme-1 in patients with chronic rhinitis. Am. J. Respir. Cell Mol. Biol. 14, 248-53.

    PubMed  Google Scholar 

  • Gajkowska, B. & Mossakowski, M. J. (1995) Localization of endothelin in the blood-brain interphase in rat hippocampus after global cerebral ischemia. Folia Neuropathol. 33, 221-30.

    PubMed  Google Scholar 

  • Giaid, A., Gibson, S. J., Herrero, M.T., Gentleman, S., Legon, S., Yanagisawa, M., Masaki, T., Ibrahim, N.B., Roberts, G.W., Rossi, M.L. & Polak, J.M. (1991) Topographical localisation of endothelin mRNA and peptide immunoreactivity in neurones of the human brain. Histochemistry 95, 303-14.

    Article  PubMed  Google Scholar 

  • Godfraind, T. (1993) Evidence for heterogeneity of endothelin receptor distribution in human coronary artery. Br. J. Pharmacol. 110, 1201-5.

    PubMed  Google Scholar 

  • Hay, D.W., Henry, P. J. & Goldie, R.G. (1993) Endothelin and the respiratory system. Trends Pharmacol. Sci. 14, 29-32.

    Article  PubMed  Google Scholar 

  • Haynes, W.G. & Webb, D. J. (1994) Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 344, 852-4.

    Article  PubMed  Google Scholar 

  • Haynes, W.G., Ferro, C.J., O'kane, K.P., Somerville, D., Lomax, C.C. & Webb, D. J. (1996) Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation 93, 1860-70.

    PubMed  Google Scholar 

  • Hemsen, A., Gillis, C., Larsson, O., Haegerstrand, A. & Lundberg, J.M. (1991) Characterization, localization and actions of endothelins in umbilical vessels and placenta of man. Acta Physiol. Scand. 143, 395-404.

    PubMed  Google Scholar 

  • Hinson, J.P., Vinson, G.P., Kapas, S. & Teja, R. (1991) The role of endothelin in the control of adrenocortical function: stimulation of endothelin release by ACTH and the effects of endothelin-1 and endothelin-3 on steroidogenesis in rat and human adrenocortical cells. J. Endocrinol. 128, 275-80.

    PubMed  Google Scholar 

  • Howard, P.G., Plumpton, C. & Davenport, A.P. (1992) Anatomical localization and pharmacological activity of mature endothelins and their precursors in human vascular tissue. J. Hypertens. 10, 1379-86.

    PubMed  Google Scholar 

  • Ikura, T., Sawamura, T., Shiraki, T., Hosokawa, H., Kido, T., Hoshikawa, H., Shimada, K., Tanzawa, K., Kobayashi S., Miwa, S. & Masaki, T. (1994) cDNA cloning and expression of bovine endothelin converting enzyme. Biochem. Biophys. Res. Commun. 203, 1417-22.

    Article  PubMed  Google Scholar 

  • Lee, M.E., De LA Monte, S.M., Ng, S.C., Bloch, K.D. & Quertermous, T. (1990) Expression of the potent vasoconstrictor endothelin in the human central nervous system. J. Clin. Invest. 86, 141-7.

    PubMed  Google Scholar 

  • Ma, K.C., Nie, X. J., Hoog, A., Olsson, Y. & Zhang, W.W. (1994) Reactive astrocytes in viral infections of the human brain express endothelin-like immunoreactivity. J. Neurol. Sci. 126, 184-92.

    Article  PubMed  Google Scholar 

  • Maguire, J. J. & Davenport, A.P. (1995) ETA receptor-mediated constrictor responses to endothelin peptides in human blood vessels in vitro. Br. J. Pharmacol. 115, 191-7.

    PubMed  Google Scholar 

  • Maguire, J. J., Kuc, R.E., O'reilly, G. & Davenport, A.P. (1994) Vasoconstrictor endothelin receptors characterised in human renal artery and vein in vitro. Br. J. Pharmacol. 113, 49-54.

    PubMed  Google Scholar 

  • Maguire, J. J., Johnson, C.M., Mockridge, J.W. & Davenport, A.P. (1997) Endothelin converting enzyme (ECE) activity in human vascular smooth muscle. Br. J. Pharmacol. 122, 1647-54.

    PubMed  Google Scholar 

  • Marciniak, S.J., Plumpton, C., Barker, P. J., Huskisson, N.S. & Davenport, A.P. (1992) Localization of immunoreactive endothelin and proendothelin in the human lung. Pulmon. Pharmacol. 5, 175-82.

    Article  Google Scholar 

  • Matsumoto, H., Suzuki, N., Kitada, C. & Fujino, M. (1994) Endothelin family peptides in human plasma and urine, their molecular forms and concentrations. Peptides 15, 505-10.

    Article  PubMed  Google Scholar 

  • Mombouli, J.V., Le, S.Q., Wasserstrum, N. & Vanhoutte, P.M. (1993) Endothelins 1 and 3 and big Endothelin-1 contract isolated human placental veins. J. Cardiovasc. Pharmacol. 22 (Suppl. 8), S278-81.

    PubMed  Google Scholar 

  • Opgaard, O.S., Adner, M., Gulbenkian, S. & Edvinsson, L. (1994) Localization of endothelin immunoreactivity and demonstration of constrictory endothelin-A receptors in human coronary arteries and veins. J. Cardiovasc. Pharmacol. 23, 576-83.

    PubMed  Google Scholar 

  • Opgenorth, T.J., Wu-Wong, J.R. & Shiosaki, K. (1992) Endothelin-converting enzymes. FASEB J. 6, 2653-9.

    PubMed  Google Scholar 

  • Pierre, L.N. & Davenport, A.P. (1995) Autoradiographic study of endothelin receptors in human cerebral arteries. J. Cardiovasc. Pharmacol. 26 (Suppl. 3), S326-8.

    PubMed  Google Scholar 

  • Plumpton, C., Kalinka, S., Martin, R.C., Horton, J.K. & Davenport, A.P. (1994) Effects of phosphoramidon and pepstatin A on the secretion of endothelin-1 and big endothelin-1 by human umbilical vein endothelial cells: measurement by two-site enzyme-linked immunosorbent assays. Clin. Sci. 87, 245-51.

    PubMed  Google Scholar 

  • Plumpton, C., Haynes, W.G., Webb, D. J. & Davenport, A.P. (1995) Phosphoramidon inhibition of the in vivo conversion of big endothelin-1 to endothelin-1 in the human forearm. Br. J. Pharmacol. 116, 1821-8.

    PubMed  Google Scholar 

  • Plumpton, C., Ashby, M.J., Kuc, R.E., O'reilly, G. & Davenport, A.P. (1996) Expression of endothelin peptides and mRNA in the human heart. Clin. Sci. 90, 37-46.

    PubMed  Google Scholar 

  • Rossi, G.P., Albertin, G., Franchin, E., Sacchetto, A., Cesari, M., Palu, G. & Pessina, A.C. (1995) Expression of the endothelin-converting enzyme gene in human tissues. Biochem. Biophys. Res. Commun. 211, 249-53.

    Article  PubMed  Google Scholar 

  • Schmidt, M., Kroger, B., Jacob, E., Seulberger, H., Subkowski, T., Otter, R., Meyer, T., Schmalzing, G. & Hillen, H. (1994) Molecular characterization of human and bovine endothelin converting enzyme (ECE-1). FEBS Lett. 356, 238-43.

    Article  PubMed  Google Scholar 

  • Seo, B., Oemar, B.S., Siebenmann, R., Von-Segesser, L. & Luscher, T.F. (1994) Both ET(A) and ET(B) receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 89, 1203-8.

    PubMed  Google Scholar 

  • Shimada, K., Takahashi, M. & Tanzawa, K. (1994) Cloning and functional expression of endothelin-converting enzyme from rat endothelial cells. J. Biol. Chem. 269, 18275-8.

    PubMed  Google Scholar 

  • Shimada, K., Matsushita, Y., Wakabayashi, K., Takahashi, M., Matsubara, A., IIJIMA, Y. & Tanzawa, K. (1995a) Cloning and functional expression of human endothelin-converting enzyme cDNA. Biochem. Biophys. Res. Commun. 207, 807-12.

    Article  PubMed  Google Scholar 

  • Shimada, K., Takahashi, M., Ikeda, M. & Tanzawa, K. (1995b) Identification and characterization of two isoforms of an endothelin-converting enzyme-1. FEBS Lett. 371, 140-4.

    Article  PubMed  Google Scholar 

  • Shimada, K., Takahashi, M., Turner, A. J. & Tanzawa, K. (1996) Rat endothelin-converting enzyme-1 forms a dimer through Cys412 with a similar catalytic mechanism and a distinct substrate binding mechanism compared with neutral endopeptidase-24.11. Biochem. J. 315, 863-7.

    PubMed  Google Scholar 

  • Takahashi, M., Fukuda, K., Shimada, K., Barnes, K., Turner, A. J., Ikeda, M., Koike, H., Yamamoto, Y. & Tanzawa, K. (1995) Localization of rat endothelin-converting enzyme to vascular endothelial cells and some secretory cells. Biochem. J. 311, 657-65.

    PubMed  Google Scholar 

  • Thornton, J.M. & Sibanda, B.L. (1983) Amino and carboxy-terminal regions in globular proteins. J. Mol. Biol. 167, 443-60.

    PubMed  Google Scholar 

  • Turner, A. J. & Murphy, L. J. (1996) Molecular pharmacology of endothelin converting enzymes. Biochem. Pharmacol. 51, 91-102.

    Article  PubMed  Google Scholar 

  • Valdenaire, O., Rohrbacher, E. & Mattei, M.G. (1995) Organization of the gene encoding the human endothelin-converting enzyme (ECE-1). J. Biol. Chem. 270, 29794-8.

    Article  PubMed  Google Scholar 

  • Warner, T.D., Schmidt, H.H., Kuk, J., Mitchell, J.A. & Murad, F. (1992) Human brain contains a metalloprotease that converts big endothelin-1 to endothelin-1 and is inhibited by phosphoramidon and EDTA. Br. J. Pharmacol. 106, 505-6.

    PubMed  Google Scholar 

  • Watanabe, Y., Naruse, M., Monzen, C., Naruse, K., Ohsumi, K., Horiuchi, J., Yoshihara, I., Kato, Y., Nakamura, N., Kato, M., Sugino, N. & Demura, H. (1991) Is big endothelin converted to endothelin-1 in circulating blood? Cardiovasc. Pharmacol. 17 (Suppl. 7), S503-5.

    Google Scholar 

  • Xu, D., Emoto, N., Giaid, A., Slaughter, C., Kaw, S., Dewit, D. & Yanagisawa, M. (1994) ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell 78, 473-85.

    Article  PubMed  Google Scholar 

  • Yorimitsu, K., Moroi, K., Inagaki, N., Saito, T., Masuda, Y., Masaki, T., Seino, S. & Kimura, S. (1995) Cloning and sequencing of a human endothelin-converting enzyme in renal adenocarcinoma (ACHN) cells producing endothelin-2. Biochem. Biophys. Res. Commun. 208, 721-7.

    Article  PubMed  Google Scholar 

  • Zhang, M. & Olsson, Y. (1995) Reactions of astrocytes and microglial cells around hematogenous metastases of the human brain. Expression of endothelin-like immunoreactivity in reactive astrocytes and activation of microglial cells. J. Neurol. Sci. 134, 26-32.

    Article  PubMed  Google Scholar 

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Davenport, A.P., Kuc, R.E., Plumpton, C. et al. Endothelin-converting enzyme in human tissues. Histochem J 30, 359–374 (1998). https://doi.org/10.1023/A:1003236628701

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