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Infection and Immunity, March 2005, p. 1543-1552, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1543-1552.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Gingipains from Porphyromonas gingivalis W83 Induce Cell Adhesion Molecule Cleavage and Apoptosis in Endothelial Cells

Shaun M. Sheets,1* Jan Potempa,2,3 James Travis,3 Carlos A. Casiano,1,4 and Hansel M. Fletcher1

Department of Biochemistry and Microbiology, School of Medicine,1 Center for Molecular Biology and Gene Therapy, Loma Linda University, Loma Linda, California,4 Department of Microbiology, Faculty of Biotechnology, Jagiellonian University, Kraków, Poland,2 Department of Biochemistry, University of Georgia, Athens, Georgia3

Received 6 July 2004/ Returned for modification 15 September 2004/ Accepted 2 November 2004

The presence of Porphyromonas gingivalis in the periodontal pocket and the high levels of gingipain activity detected in gingival crevicular fluid could implicate a role for gingipains in the destruction of the highly vascular periodontal tissue. To explore the effects of these proteases on endothelial cells, we exposed bovine coronary artery endothelial cells and human microvascular endothelial cells to gingipain-active extracellular protein preparations and/or purified gingipains from P. gingivalis. Treated cells exhibited a rapid loss of cell adhesion properties that was followed by apoptotic cell death. Cleavage of N- and VE-cadherin and integrin ß1 was observed in immunoblots of cell lysates. There was a direct correlation between the kinetics of cleavage of N- and VE-cadherin and loss of cell adhesion properties. Loss of cell adhesion, as well as N- and VE-cadherin and integrin ß1 cleavage, could be inhibited or significantly delayed by preincubation of P. gingivalis W83 gingipain-active extracellular extracts with the cysteine protease inhibitor N{alpha}-p-tosyl-L-lysine chloromethylketone. Furthermore, purified gingipains also induced endothelial cell detachment and apoptosis. Apoptosis-associated events, including annexin V positivity, caspase-3 activation, and cleavage of the caspase substrates poly(ADP-ribose) polymerase and topoisomerase I (Topo I), were observed in endothelial cells after detachment. All of the effects observed were correlated with the different levels of cysteine-dependent proteolytic activity of the extracts tested. Taken together, these results indicate that gingipains from P. gingivalis can alter cell adhesion molecules and induce endothelial cell death, which could have implications for the pathogenicity of this organism.

* Corresponding author. Mailing address: Department of Biochemistry and Microbiology, School of Medicine, Loma Linda University, Loma Linda, CA 92350. Phone: (909) 558-4472. Fax: (909) 558-4035. E-mail: ssheets04b{at}som.llu.edu.

Editor: V. J. DiRita

Infection and Immunity, March 2005, p. 1543-1552, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1543-1552.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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