Bartonella-associated endothelial proliferation depends on inhibition of apoptosis.
Bartonella is a Gram-negative pathogen that is unique among bacteria in being able to induce angioproliferative lesions. Cultured human endothelial cells have provided an in vitro system in which to study the basis of angioproliferation. Previous studies have attributed the organism's ability to induce angioproliferative lesions to direct mitotic stimulation of endothelial cells by these bacteria. Here we show that Bartonella inhibits apoptosis of endothelial cells in vitro, and that its ability to stimulate proliferation of endothelial cells depends to a large extent on its antiapoptotic activity. Bartonella suppresses both early and late events in apoptosis, namely caspase activation and DNA fragmentation, respectively. Its ability to inhibit death of endothelial cells after serum starvation can be recapitulated by media conditioned by bacteria, indicating that direct cell contact is not necessary. Among tested strains, the activity is produced only by Bartonella species that are significant human pathogens and are associated with angioproliferative lesions. We suggest that endothelial cells normally respond to infection by undergoing apoptosis and that Bartonella evolved the antiapoptotic activity to enhance survival of the host cells and therefore itself. We propose that Bartonella's antiapoptotic mechanism accounts at least in part for its ability to induce vascular proliferation in vivo.
Kirby
James E
JE
Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, RN270G, Boston, MA 02215, USA. jekirby@caregroup.harvard.edu
Nekorchuk
Dawn M
DM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001473:Bartonella / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D017077:Culture Media, Conditioned; D004285:Dogs; D004730:Endothelium, Vascular / Q000166:cytology*; D008938:Mitosis
D000590:Amino Acid Chloromethyl Ketones; D017077:Culture Media, Conditioned; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone