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Licensed Unlicensed Requires Authentication Published by De Gruyter August 8, 2005

A possible alternative mechanism of kinin generation in vivo by cathepsin L

  • Luciano Puzer , Juliana Vercesi , Marcio F.M. Alves , Nilana M.T. Barros , Mariana S. Araujo , Maria Aparecida Juliano , Marina L. Reis , Luiz Juliano and Adriana K. Carmona
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We investigated the ability of cathepsin L to induce a hypotensive effect after intravenous injection in rats and correlated this decrease in blood pressure with kinin generation. Simultaneously with blood pressure decrease, we detected plasma kininogen depletion in the treated rats. The effect observed in vivo was abolished by pre-incubation of cathepsin L with the cysteine peptidase-specific inhibitor E-64 (1 μM) or by previous administration of the bradykinin B2 receptor antagonist JE049 (4 mg/kg). A potentiation of the hypotensive effect caused by cathepsin L was observed by previous administration of the angiotensin I-converting enzyme inhibitor captopril (5 mg/kg). In vitro studies indicated that cathepsin L excised bradykinin from the synthetic fluorogenic peptide Abz-MTSVIRRPPGFSPFRAPRV-NH2, based on the Met375–Val393 sequence of rat kininogen (Abz=o-aminobenzoic acid). In conclusion, our data indicate that in vivo cathepsin L releases a kinin-related peptide, and in vitro experiments suggest that the kinin generated is bradykinin. Although it is well known that cysteine proteases are strongly inhibited by kininogen, cathepsin L could represent an alternative pathway for kinin production in pathological processes.


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Araujo, M.C., Melo, R.L., Cesari, M.H., Juliano, M.A., Juliano, L., and Carmona, A.K. (2000). Peptidase specificity characterization of C- and N-terminal catalytic sites of angiotensin I-converting enzyme. Biochemistry39, 8519–8525.10.1021/bi9928905Search in Google Scholar

Assfalg-Machleidt, I., Billing, A., Frohlich, D., Nast-Kolb, D., Joka, T., Jochum, M., and Machleidt, W. (1992). The role of the kininogens as cysteine proteinase inhibitors in local and systemic inflammation. Agents Actions (suppl. 38), 312–321.10.1007/978-3-0348-7321-5_40Search in Google Scholar

Barrett, A.J. and Kirschke, H. (1981). Cathepsin B, cathepsin H, and cathepsin L. Methods Enzymol.80, 535–561.10.1016/S0076-6879(81)80043-2Search in Google Scholar

Barros, N.M.T., Tersariol I.L.S., Oliva, M.L.V., Araujo, M.S., Sampaio, C.A.M., Juliano, L., and Motta, G. (2004a). High molecular weight kininogen as substrate for cathepsin B. Biol. Chem.385, 551–555.10.1515/BC.2004.066Search in Google Scholar

Barros, N.T, Puzer, L., Tersariol, I.L.S., Oliva, M.L.V., Sampaio, C.A.M., Carmona, A.K., and Mota, G. (2004b). Plasma prekallikrein/kallikrein processing by lysosomal cysteine proteases. Biol. Chem.385, 1087–1091.10.1515/BC.2004.141Search in Google Scholar

Blais, C. Jr., Marceaub, F., Rouleauc, J.L., and Adama, A. (2000). The kallikrein-kininogen-kinin system: lessons from the quantification of endogenous kinins. Peptides21, 1903–1940.10.1016/S0196-9781(00)00348-XSearch in Google Scholar

Carmona, E., Dufour, É., Plouffe, C., Takebe, S., Manson, P., Mort, S.M. and Ménard, R. (1996). Potency and selectivity of the cathepsin L propeptide as an inhibitor of cysteine proteases. Biochemistry35, 8149–8157.10.1021/bi952736sSearch in Google Scholar

Chapman, H.A., Riese, R.J., and Shi, G.P. (1997). Emerging roles for cysteine proteases in human biology. Annu. Rev. Physiol.59, 63–88.10.1146/annurev.physiol.59.1.63Search in Google Scholar

Cordova, M., Jara, J., Del Nery, E., Hirata, Y.I., Araujo, M.S., Carmona, A.K., Juliano, M.A., and Juliano, L. (2001). Characterization of two cysteine proteinases secreted by Fasciola hepatica and demonstration of their kininogenase activity. Mol. Biochem. Parasitol.116, 109–115.10.1016/S0166-6851(01)00309-7Search in Google Scholar

Dehrmann, F.M., Coetzer, T.H., Pike, R.N., and Dennison, C. (1995). Mature cathepsin L is substantially active in the ionic milieu of the extracellular medium. Arch. Biochem. Biophys.324, 93–98.10.1006/abbi.1995.9924Search in Google Scholar PubMed

Del Nery, E., Juliano, M.A., Lima, A.P.C., Scharfstein, J., and Juliano, L. (1997). Kininogenase activity by the major cysteine proteinase (cruzain) from Trypanosoma cruzi.J. Biol. Chem.272, 25713–25718.10.1074/jbc.272.41.25713Search in Google Scholar

Desmazes, C., Gauthier, F., and Lalmanach, G. (2001). Cathepsin L, but not cathepsin B, is as potential kininogenase. Biol. Chem.382, 811–815.10.1515/bchm.2001.382.5.811Search in Google Scholar

Desmazes, C., Galineau, L., Gauthier, F., Brömme, D., and Lalmanach, G. (2003). Kininogen-derived peptides for investigating the putative vasoactive properties of human cathepsins K and L. Eur. J. Biochem.270, 171–178.10.1046/j.1432-1033.2003.03382.xSearch in Google Scholar

Diniz, C.R. and Carvalho, I.F. (1963). A micromethod for determination of bradykininogen under several conditions. Ann. NY Acad. Sci.104, 77–78.10.1111/j.1749-6632.1963.tb17654.xSearch in Google Scholar

Gabrijelcic, D., Annan-Prah, A., Rodic, B., Rozman, B., Cotic, V., and Turk, V. (1990). Determination of cathepsins B and H in sera and synovial fluids of patients with different joint diseases. J. Clin. Chem. Clin. Biochem.28, 49–53.10.1515/cclm.1990.28.3.149Search in Google Scholar

Hernandez, C.C., Donadi, E.A., and Reis, M.L. (1998). Kininogen-kallikrein-kinin system in plasma and saliva of patients with Sjogren's syndrome. J. Rheumatol.25, 2381–2384.Search in Google Scholar

Herwald, H., Collin, M., Muller-Esterl, W., and Bjorck, L. (1996). Streptococcal cysteine proteinase releases kinins: a novel virulence mechanism. J. Exp. Med.184, 665–673.10.1084/jem.184.2.665Search in Google Scholar

Imamura, T., Pike, R.N., Potempa, J., and Travis, J. (1994). Pathogenesis of periodontitis – a major arginine-specific cysteine proteinase from Porphyromonas gingivalis induces vascular-permeability enhancement through activation of the kallikrein-kinin pathway. J. Clin. Invest.423, 361–377.10.1172/JCI117330Search in Google Scholar

Kirschke, H., Wiederanders, B., Brömme, D., and Rinne, A. (1989). Cathepsin S from bovine spleen. Purification, distribution, intracellular localization and action on proteins. Biochem. J.264, 467–473.Search in Google Scholar

Kos, J. and Lah, T.T. (1998). Cysteine proteinases and their inhibitors: target proteins for prognosis, diagnosis and therapy in cancer. Oncol. Rep.5, 1349–1361.10.3892/or.5.6.1349Search in Google Scholar

Leatherbarrow, R.J. (1992). Grafit Version 3.0 (Staines, UK: Erithacus Software Ltd).Search in Google Scholar

Murta, A.C.M., Persechini, P.M., Padron, T.S., Souza, W., Guimarães, J.A., and Scharfstein, J. (1990). Stuctural and functional identification of GP 57/51 antigen of Trypanosoma cruzi as a cysteine proteinase. Mol. Biochem. Parasitol.43, 27–38.10.1016/0166-6851(90)90127-8Search in Google Scholar

Prado, J.L. (1970). In: Handbook of Experimental Pharmacology, O. Eichler, A. Farah, H. Herker and A.D. Welch, eds. (Berlin, Germany: Springer-Verlag), pp. 56–192.Search in Google Scholar

Puzer, L., Cotrin, S.S., Alves, M.F.M., Egborge, T., Araújo, M.S., Juliano, M.A., Juliano, L., Brömme, D., and Carmona, A.K. (2004). Comparative substrate specificity analysis of recombinant human cathepsin V and cathepsin L. Arch. Biochem. Biophys.430, 274–283.10.1016/ in Google Scholar PubMed

Rocha e Silva, M., Beraldo, W.T., Rosenfeld, G. (1949). Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and by trypsin. Am. J. Physiol.156,261–273.10.1152/ajplegacy.1949.156.2.261Search in Google Scholar

Rothschild, A.M., Boden, G., and Colman, R.W. (1996). Kininogen changes in human plasma following a test meal or insulin administration. Immunopharmacology33, 354–358.10.1016/0162-3109(96)00081-1Search in Google Scholar

Scharfstein, J., Schmitz, V., Morandi, V., Capella, M.M., Lima, A.P., Morrot, A., Juliano, L., and Müller-Esterl, W. (2000). Host cell invasion by Trypanosoma cruzi is potentiated by activation of bradykinin B-2 receptors. J. Exp. Med.192, 1289–1300.10.1084/jem.192.9.1289Search in Google Scholar

Scott, C.F., Whitaker, E.J., Hammond, B.F., and Colman, R.W. (1993). Purification and characterization of a potent 70-kDa thiol lysylproteinase (Lys-gingivain) from Porphyromonas gingivalis that cleaves kininogens and fibrinogen. J. Biol. Chem.268, 7935-7942.10.1016/S0021-9258(18)53048-9Search in Google Scholar

Sloane, B.F., Moin, K., and Lah, T.T. (1994). Lysosomal enzymes and their endogenous inhibitors in neoplasia. In: Biochemical and Molecular Aspects of Selected Cancers, T.G. Pretlow and T.P. Pretlow, eds. (New York, USA: Academic Press), pp. 411–466.Search in Google Scholar

Turk, B., Turk, V., and Turk, D. (1997). Structural and functional aspects of papain-like cysteine proteinases and their protein inhibitors. Biol. Chem.378, 141–150.Search in Google Scholar

Turk, B., Turk, D., and Turk, V. (2000). Lysosomal cysteine proteases: more than scavengers. Biochim. Biophys. Acta1477, 98–111.10.1016/S0167-4838(99)00263-0Search in Google Scholar

Published Online: 2005-08-08
Published in Print: 2005-07-01

©2005 by Walter de Gruyter Berlin New York

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