Abstract
Chronic inflammatory diseases, such as periodontal disease, associate with adverse wound healing in response to myocardial infarction (MI). The goal of this study was to elucidate the molecular basis for impaired cardiac wound healing in the setting of periodontal-induced chronic inflammation. Causal network analysis of 168 inflammatory and extracellular matrix genes revealed that chronic inflammation induced by a subseptic dose of Porphyromonas gingivalis lipopolysaccharide (LPS) exacerbated infarct expression of the proinflammatory cytokine Ccl12. Ccl12 prevented initiation of the reparative response by prolonging inflammation and inhibiting fibroblast conversion to myofibroblasts, resulting in diminished scar formation. Macrophage secretion of Ccl12 directly impaired fibronectin and collagen deposition and indirectly stimulated collagen degradation through upregulation of matrix metalloproteinase-2. In post-MI patients, circulating LPS levels strongly associated with the Ccl12 homologue monocyte chemotactic protein 1 (MCP-1). Patients with LPS levels ≥ 1 endotoxin units (EU)/ml (subseptic endotoxemia) at the time of hospitalization had increased end diastolic and systolic dimensions compared with post-MI patients with < 1 EU/ml, indicating that low yet pathological concentrations of circulating LPS adversely impact post-MI left ventricle (LV) remodeling by increasing MCP-1. Our study provides the first evidence to our knowledge that chronic inflammation inhibits reparative fibroblast activation and generates an unfavorable cardiac-healing environment through Ccl12-dependent mechanisms.
Highlights
Periodontal disease (PD) is associated with adverse wound healing in response to injury across organ systems, including poor cardiac responses to myocardial infarction (MI) [1,2,3,4,5,6]
We combined genomic, proteomic, biochemical, and pathophysiological evaluations in mice and human MI subjects to elucidate the role of PD-induced chronic inflammation on cardiac wound healing after MI
Our study is the first to our knowledge to reveal that chronic inflammation increases macrophage secretion of Ccl12 to inhibit reparative fibroblast activation and extracellular matrix (ECM) deposition (Figure 9)
Summary
Periodontal disease (PD) is associated with adverse wound healing in response to injury across organ systems, including poor cardiac responses to myocardial infarction (MI) [1,2,3,4,5,6]. MI incidence correlates with the number of pockets > 4 mm deep, bleeding sites after probing, and severity of tooth loss, even after adjustment for known cardiovascular risk factors (e.g., smoking, diabetes, or hypertension) [4]. PD is caused by chronic inflammation of tissues surrounding the teeth, in response to bacterial biofilm accumulation [7]. Especially endotoxins, are key drivers of inflammation and PD development [8]. It is hypothesized that the link between PD and cardiovascular disease (CVD) is due to chronic inflammatory mechanisms initiated by the bacteria products present within periodontal lesions [9]. While the oral health and CVD epidemiological correlation is quite strong, the mechanistic link between oral health and MI response is not fully understood
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