Role of β-adrenergic signaling in the development of Porphyromonas gingivalis lipopolysaccharide-induced cardiac dysfunction in mice.

The aims of the present study were to investigate the changes of cardiac dysfunction induced by Porphyromonas gingivalis lipopolysaccharide (PG-LPS, 0.8 mg/kg/day for a week) in mice, and to elucidate the underlying mechanisms, as well as to evaluate the effect of the non-selective β-blocker propranolol (PPL) on the PG-LPS-induced changes. Since little is known about the involvement of the sympathetic nervous system in the development or exacerbation of periodontitis-induced cardiovascular disease (CVD), we first examined the effects of PG-LPS on heart variability. The normalized low frequency, an index of sympathetic nervous activity, was significantly increased after administration of PG-LPS, with an increase of mean heart rate at all time points examined. We then evaluated the effects of PPL on these PG-LPS-induced changes. Left ventricular ejection fraction was significantly decreased from baseline (from 66 ± 1.1 to 57 ± 2.3%) by PG-LPS, while PPL ameliorated the dysfunction. PG-LPS significantly increased cardiac fibrosis (approximately 3.1-fold), myocyte apoptosis (approximately 5.1-fold) and oxidative DNA damage (approximately sixfold), and PPL blocked these changes. Mechanistic studies suggested that impairment of cardiac function in PG-LPS-treated mice involves activation of NADPH oxidase 4/receptor-interacting protein 3/calmodulin kinase II signaling, leading to Ca2+ leakage from sarcoplasmic reticulum mediated by phosphorylation of phospholamban and ryanodine receptor 2. Overall, our results suggested that activation of β-adrenergic signaling might play an important role in the development of periodontitis-induced CVD.