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Gingipains from Porphyromonas gingivalis W83 Synergistically Disrupt Endothelial Cell Adhesion and Can Induce Caspase-Independent Apoptosis

Department of Biochemistry and Microbiology, School of Medicine, Loma Linda University, Loma Linda, California,¹ Department of Microbiology, Faculty of Biotechnology, Jagiellonian University, Kraków, Poland,² Department of Biochemistry, University of Georgia, Athens, Georgia,³ Center for Molecular Biology and Gene Therapy, Loma Linda University, Loma Linda, California⁴

Received 18 July 2005/ Returned for modification 12 December 2005/ Accepted 6 July 2006

We have shown previously that gingipains from Porphyromonas gingivalis W83 can induce cell detachment, cell adhesion molecule (CAM) cleavage, and apoptosis in endothelial cells; however, the specific roles of the individual gingipains are unclear. Using purified gingipains, we determined that each of the gingipains can cleave CAMs to varying degrees with differing kinetics. Kgp and HRgpA work together to quickly detach endothelial cells. Interestingly, in the absence of active caspases, both gingipain-active W83 extracts and purified HRgpA and RgpB induce apoptotic morphology, suggesting that the gingipains can induce both caspase-dependent and caspase-independent apoptosis. Using z-VAD-FMK to inhibit Kgp activity and leupeptin to inhibit Rgp activity in gingipain-active W83 extracts, we investigated the relative significance of the synergistic role of the gingipains. z-VAD-FMK or leupeptin delayed, but did not inhibit, cell detachment induced by gingipain-active W83 extracts or purified gingipains. There was partial cleavage of N-cadherin and cleavage of VE-cadherin was not inhibited. Degradation of integrin ß1 was inhibited only in the presence of z-VAD-FMK. These results further clarify the role P. gingivalis plays in tissue destruction occurring in the periodontal pocket.

Editor: V. J. DiRita