Gingipains from the Periodontal Pathogen Porphyromonas gingivalis Play a Significant Role in Regulation of Angiopoietin 1 and Angiopoietin 2 in Human Aortic Smooth Muscle Cells

Abstract

Angiopoietin 1 (Angpt1) and angiopoietin 2 (Angpt2) are the ligands of tyrosine kinase (Tie) receptors, and they play important roles in vessel formation and the development of inflammatory diseases, such as atherosclerosis. Porphyromonas gingivalis is a Gram-negative periodontal bacterium that is thought to contribute to the progression of cardiovascular disease. The aim of this study was to investigate the role of P. gingivalis infection in the modulation of Angpt1 and Angpt2 in human aortic smooth muscle cells (AoSMCs). We exposed AoSMCs to wild-type (W50 and 381), gingipain mutant (E8 and K1A), and fimbrial mutant (DPG-3 and KRX-178) P. gingivalis strains and to different concentrations of tumor necrosis factor (TNF). The atherosclerosis risk factor TNF was used as a positive control in this study. We found that P. gingivalis (wild type, K1A, DPG3, and KRX178) and TNF upregulated the expression of Angpt2 and its transcription factor ETS1, respectively, in AoSMCs. In contrast, Angpt1 was inhibited by P. gingivalis and TNF. However, the RgpAB mutant E8 had no effect on the expression of Angpt1, Angpt2, or ETS1 in AoSMCs. The results also showed that ETS1 is critical for P. gingivalis induction of Angpt2. Exposure to Angpt2 protein enhanced the migration of AoSMCs but had no effect on proliferation. This study demonstrates that gingipains are crucial to the ability of P. gingivalis to markedly increase the expressed Angpt2/Angpt1 ratio in AoSMCs, which determines the regulatory role of angiopoietins in angiogenesis and their involvement in the development of atherosclerosis. These findings further support the association between periodontitis and cardiovascular disease.

The role of toll‐like and protease‐activated receptors and associated intracellular signaling in Porphyromonas gingivalis‐infected gingival fibroblasts

“…Understanding the intracellular signaling events and the importance of PAR1, PAR2, TLR2, and TLR4 in gingival fibroblasts challenged by P. gingivalis , a keystone agent in periodontitis, would increase the knowledge of how innate immune responses are regulated in periodontitis. Studies by our group and others indicate a link between periodontitis and cardiovascular diseases, as well as other diseases . Effective treatment and prevention of periodontitis would, therefore, not only improve oral health but could also reduce the risk of cardiovascular diseases and other periodontitis‐associated diseases with an inflammatory background.…”

Environmental lead effects on gene expression in oral epithelial cells

“…The ETS proto‐oncogene 1 transcription factor was upregulated following biofilm challenge and directly controls the expression of cytokine and chemokine genes in a wide variety of cells . It has been reported as 1 of a set of master regulatory genes in periodontitis, and its enhanced expression confirmed from in vivo tissue samples and in vitro studies following challenge with P. gingivalis . Interleukin enhancing binding factor 3 (IL‐F3) can regulate the transcription of IL‐2 and a single report identified upregulation of the IL‐F3 protein in monocytes challenged with P. gingivalis .…”

“…105 It has been reported as 1 of a set of master regulatory genes in periodontitis, 106 and its enhanced expression confirmed from in vivo tissue samples 95,106,107 and in vitro studies following challenge with P. gingivalis. 107 Interleukin enhancing binding factor 3 (IL-F3) can regulate the transcription of IL-2 and a single report identified upregulation of the IL-F3 protein in monocytes challenged with P. gingivalis. 108 Interferon regulatory factor 1 (IRF1) functions as a transcription activator of genes induced by various interferons and can affect macrophages, Th1 cell development and maturation, the differentiation and maturation of dendritic cells, and suppressing Treg cell development.…”

Cellular Response Mechanisms in Porphyromonas gingivalis Infection

“…For example, P. gingivalis upregulates genes involved in proliferation, for example, the TGFβ1 pathway and production of matrix proteins, but downregulates pro-inflammatory genes, such as those involved in IL-1β, IL-6, and CXCL8 production. P. gingivalis also caused a dramatic increase in the expression of angiopoietin2 (ANGPT2), which is highly corre lated with inflammation and atherosclerosis, whereas ANGPT1, inhibitor of inflammation, was downregulated [85,86]. These effects are mediated via gingipain R, possibly through PAR signaling.…”