Role of TLR4 signaling on Porphyromonas gingivalis LPS-induced cardiac dysfunction in mice

Abstract

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.

Vidarabine, an anti-herpes agent, improves Porphyromonas gingivalis lipopolysaccharide-induced cardiac dysfunction in mice

“…2 a). PG-LPS treatment significantly increased the area of fibrosis in cardiac muscle (Control [ n = 6] vs. PG-LPS [ n = 7]: 0.98 ± 0.46 vs. 1.86 ± 0.34%, P < 0.01 by one-way ANOVA followed by Tukey’s post hoc test), in accordance with our previous findings [ 18 , 20 ] (Fig. 2 b).…”

“…All LV dimensions calculated using the Teichholz formula in wild-type control (12-week-old C57BL/6 mice) were consistent with those reported in previous studies by us [ 20 ] and another group [ 29 ].…”

“…We recently established that activation of toll-like receptor 4 signaling in mice induced by PG-LPS at the dose used in this study causes cardiac dysfunction, myocyte apoptosis and fibrosis in cardiac muscle, leading to abundant production of ROS and Ca 2+ leakage from sarcoendoplasmic reticulum due to CaMKII-mediated phosphorylation of PLN (at Thr-17) [ 20 ]. We also demonstrated that the cAMP-CaMKII pathway is activated in mice treated with PG-LPS, as used in this study [ 18 ].…”

“…All experiments were performed on male 12-week-old C57BL/6 mice obtained from CLEA Japan (Tokyo, Japan). Mice were group-hosed at 23 °C under a 12–12 light/dark cycle with lights on at 8:00 AM in accordance with standard conditions for mouse studies by our group [ 20 – 22 ]. Both food and water were available ad libitum.…”

Effects of the oral angiotensin-converting enzyme inhibitor captopril on occlusal-disharmony-induced cardiac dysfunction in mice

“…All experiments were performed on male 16-week-old C57BL/6 mice obtained from CLEA Japan (Tokyo, Japan). Mice were group-housed at 23°C under a 12-12 light/dark cycle with lights on 8:00 AM in accordance with the standard conditions for mouse studies by our group [15][16][17]50 . Both food and water were available ad libitum.…”