PT  - JOURNAL ARTICLE
AU  - Ichiro Matsuo
AU  - Naoya Kawamura
AU  - Yoshiki Ohnuki
AU  - Kenji Suita
AU  - Misao Ishikawa
AU  - Takehiro Matsubara
AU  - Yasumasa Mototani
AU  - Aiko Ito
AU  - Yoshio Hayakawa
AU  - Megumi Nariyama
AU  - Akinaka Morii
AU  - Kenichi Kiyomoto
AU  - Michinori Tsunoda
AU  - Kazuhiro Gomi
AU  - Satoshi Okumura
TI  - Role of TLR4 signaling on <em>Porphyromonas gingivalis</em> LPS-induced cardiac dysfunction in mice
AID  - 10.1101/2021.10.07.463544
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.07.463544
4099  - http://biorxiv.org/content/early/2021/10/07/2021.10.07.463544.short
4100  - http://biorxiv.org/content/early/2021/10/07/2021.10.07.463544.full
AB  - Oral infections, particularly periodontitis, are a well-established risk factor for cardiovascular diseases, although the molecular mechanisms involved remain elusive. The aims of the present study were to investigate the effects of lipopolysaccharide derived from Porphyromonas gingivalis (PG-LPS) on cardiac function in mice, and to elucidate the underlying mechanisms. Mice (C57BL/6) were injected with PG-LPS (0.8 mg/kg/day) with or without an inhibitor of Toll-like receptor 4 (TLR4) signaling (TAK-242, 0.8 mg/kg/day) for 4 weeks. Left ventricular ejection function was significantly decreased at 1 week (from 67 ± 0.5 to 58 ± 1.2 %) and remained low at 4 weeks (57 ± 1.0 %). The number of apoptotic myocytes was increased (approximately 7.4-fold), the area of fibrosis was increased (approximately 3.3-fold) and the number of 8-hydroxydeoxyguanosine-positive myocytes, a sensitive indicator of oxidative DNA damage, was increased (approximately 7.6-fold) at 4 weeks in the heart of PG-LPS treated mice. However, levels of various serum pro-inflammatory cytokines in PG-LPS-treated mice were similar to those in control mice. The impairment of cardiac function in PG-LPS-treated mice appears to involve activation of TLR4-NADPH oxidase (NOX) 4 signaling, leading to abundant production of reactive oxygen species and Ca2+ leakage from sarcoplastic reticulumn induced by calmodulin kinase II (CaMKII)-mediated phosphorylation of phospholamban (at Thr-17) and ryanodine receptor 2 (at Ser-2448). Pharmacological inhibition of TLR4 with TAK-242 attenuated the changes in cardiac function in PG-LPS-treated mice. Our results indicate that TLR4-NOX4 signaling may be a new therapeutic target for treatment of cardiovascular diseases in patients with periodontitis.Competing Interest StatementThe authors have declared no competing interest.