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Journal of Biochemistry Advance Access originally published online on October 8, 2006
Journal of Biochemistry 2006 140(5):713-723; doi:10.1093/jb/mvj202
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© 2006 The Japanese Biochemical Society.

ARTICLE

Selective Proteolysis of Apolipoprotein B-100 by Arg-Gingipain Mediates Atherosclerosis Progression Accelerated by Bacterial Exposure

Munetaka Hashimoto, Tomoko Kadowaki, Takayuki Tsukuba and Kenji Yamamoto*

Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582

* To whom correspondence should be addressed. Tel: +81-92-642-6337, Fax: +81-92-642-6342, E-mail: kyama{at}dent.kyushu-u.ac.jp

Epidemiological studies suggest the association of periodontal infections with atherosclerosis, however, the mechanism underlying this association remains poorly understood. Porphyromonas gingivalis is the primary etiologic agent of adult periodontitis and produces a unique class of cysteine proteinases consisting of Arg-gingipain (Rgp) and Lys-gingipain (Kgp). To elucidate key mechanisms for progression of atherosclerosis by P. gingivalis infection, we tested the effects of the disruption of genes encoding Rgp and/or Kgp and inhibitors specific for the respective enzymes on atherosclerosis progression in apolipoprotein E–knockout mice. Repeated intravenous injection of wild-type P. gingivalis resulted in an increase in atherosclerotic lesions as well as an increase in the serum LDL cholesterol and a decrease of HDL cholesterol in these animals. LDL particles in P. gingivalis–injected animals were modified as a result of selective proteolysis of apoB-100 in LDL particles. This modification of LDL by P. gingivalis resulted in an increase in LDL uptake by macrophages and consequent foam cell formation in vitro. The atherosclerotic changes induced by P. gingivalis infection were attenuated by disruption of Rgp-encoding genes or by an Rgp-specific inhibitor. Our results indicate that degradation of apoB-100 by Rgp plays a crucial role in the promotion of atherosclerosis by P. gingivalis infection.


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K. Yamatake, M. Maeda, T. Kadowaki, R. Takii, T. Tsukuba, T. Ueno, E. Kominami, S. Yokota, and K. Yamamoto
Role for Gingipains in Porphyromonas gingivalis Traffic to Phagolysosomes and Survival in Human Aortic Endothelial Cells
Infect. Immun., May 1, 2007; 75(5): 2090 - 2100.
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