Circulating Porphyromonas gingivalis lipopolysaccharide resets cardiac homeostasis in mice through a matrix metalloproteinase-9-dependent mechanism

Abstract

Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) circulates systemically in over 50% of periodontal disease (PD) patients and is associated with increased matrix metalloproteinase (MMP)-9. We hypothesized that low systemic Pg-LPS would stimulate an inflammatory response in the left ventricle (LV) through MMP-9, leading to a decrease in cardiac function. Wild-type (WT) and MMP-9 null mice (4–7 months old) were exposed for 1 or 28 days to low dose Pg-LPS or saline (n ≥ 6/group). MMP-9 significantly increased in WT mice LV at 1 and 28 days of exposure, compared to control (P < 0.05 for both). Fractional shortening decreased subtly yet significantly in WT mice by day 28 (31 ± 1%) compared to control (35 ± 1%; P < 0.05), and this decrease was attenuated in null (34 ± 1%) mice. Plasma cardiac troponin I levels were elevated in WT mice at day 28. Macrophage-related factors increased over twofold in WT plasma and LV after day 1 (monocyte chemoattractant protein-5, macrophage inflammatory protein (MIP)-1α, MIP-1γ, stem cell factor, Ccl12, Ccl9, Il8rb, Icam1, Itgb2, and Spp1; all P < 0.05), indicating a moderate inflammatory response. Levels returned to baseline by day 28, suggesting tolerance to Pg-LPS. In contrast, macrophage-related factors remained elevated in day 28 null mice, indicating a sustained defense against Pg-LPS stimulation. Consistent with these findings, LV macrophage numbers increased in both groups at day 1 and returned to baseline by day 28 in the WT mice only. Major histocompatibility complex (MCH) II remained elevated in the null group at day 28, confirming Pg-tolerance in the WT. Interestingly Il-1α, a regulator of macrophage immunosuppression, increased in the plasma of WT mice only on day 28, suggesting that Il-1α plays a role in tolerance in a MMP-9-dependent manner. In conclusion, circulating Pg-LPS induced tolerance in WT mice, resulting in significant LV changes and subtle cardiac dysfunction. MMP-9 played a major role in the regulation of chronic systemic inflammation and associated cardiac dysfunction.