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

• Published in: PloS one 2022-06, Vol.17 (6), p.e0258823-e0258823
• Main Authors: Matsuo, Ichiro, Kawamura, Naoya, Ohnuki, Yoshiki, Suita, Kenji, Ishikawa, Misao, Matsubara, Takehiro, Mototani, Yasumasa, Ito, Aiko, Hayakawa, Yoshio, Nariyama, Megumi, Morii, Akinaka, Kiyomoto, Kenichi, Tsunoda, Michinori, Gomi, Kazuhiro, Okumura, Satoshi
• Format: Article
• Language: English
• Subjects: 8-Hydroxydeoxyguanosine; Analysis; Antibodies; Apoptosis; Bacterial infections; Biology and Life Sciences; Ca2+/calmodulin-dependent protein kinase II; Calcium ions; Calcium-binding protein; Calcium-binding proteins; Calmodulin; Cardiovascular diseases; Care and treatment; Cytokines; Deoxyribonucleic acid; Diagnosis; DNA; DNA damage; E coli; Experiments; Fibrosis; Gram-negative bacteria; Health risks; Heart failure; Infections; Inflammation; Kinases; Laboratory animals; Lipopolysaccharides; Medicine and Health Sciences; Molecular mechanics; Molecular modelling; Myocytes; NAD(P)H oxidase; NOX4 protein; Oxygen; Periodontitis; Phospholamban; Phosphorylation; Porphyromonas gingivalis; Proteins; Reactive oxygen species; Research and Analysis Methods; Risk analysis; Risk factors; Sepsis; Signaling; Therapeutic targets; TLR4 protein; Toll-like receptors; Tumor necrosis factor-TNF; Ventricle
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0258823

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.