Cyclic di-AMP Rescues Porphyromonas gingivalis–Aggravated Atherosclerosis

Abstract

Growing evidence demonstrates the relationship between periodontitis and atherosclerotic cardiovascular diseases. The periodontal pathogen Porphyromonas gingivalis (Pg) has been shown to contribute to the progression of atherosclerosis. Cyclic diadenylate monophosphate (c-di-AMP) has been widely studied as an immune adjuvant for tumor immunotherapy, given its ability to activate the stimulator of interferon genes (STING) and regulate trained immunity. This study sought to elucidate the role of c-di-AMP in Pg-associated atherosclerosis. Periodontitis and atherosclerosis mouse models were established by ligature application around maxillary second molars and feeding ApoE knockout mice with a high-fat diet. We found that periodontitis and atherosclerosis were more severe in mice exposed to Pg than mice that underwent ligature placement only, while prophylactic treatment with c-di-AMP activated trained immunity and elicited significant alleviation of alveolar bone resorption, as well as reduced blood lipid levels and atherosclerotic plaque accumulation. After 3 mo of intervention, c-di-AMP limited the elevation of cytokines interleukin (IL)–6, IL-1β, tumor necrosis factor α, and interferon β; extracellular matrix remodeling enzymes MMP-2 and MMP-9; and adhesion molecules ICAM-1 and VCAM-1 gene expression. The mechanism underlying Pg-aggravated atherosclerosis may be attributed to changes in microbiota composition in oral and aortic plaques and excess inflammatory response, whereas c-di-AMP could prevent the effects of Pg infection due to its potential ability to activate trained immunity and regulate microecological balance. Our findings suggest a positive role of c-di-AMP in alleviating Pg-aggravated atherosclerosis by regulating the immune response and influencing the local microenvironment.

Computational analysis of curcumin‐mediated alleviation of inflammation in periodontitis patients with experimental validation in mice

“…The CTR and LIP groups were given equivalent volumes of olive oil. For LIP, mice were anaesthetized with inhaled isoflurane and a 5-0 ligature wire was subsequently placed around the bilateral maxillary second molars (K. Liu et al, 2023;Wu et al, 2023).…”

The Roles of Periodontal Bacteria in Atherosclerosis

“…Exposure to Pg induces the increased expression of these adhesion molecules and attracts a large number of monocytes to accumulate in the subendothelium of the artery, which results in extensive secretion of inflammatory factors and exacerbates vascular and systemic inflammation [ 65 , 91 ]. Cyclic diadenylate monophosphate (c-di-AMP) can mitigate the effect of Pg on AS by activating trained immunity and regulating microecological balance, including relieving the elevation in gene expression of IL-6, IL-1β, TNF-α, and interferon β; ECM remodeling enzymes matrix metalloproteinase (MMP)-2 and MMP-9; and adhesion molecules ICAM-1 and VCAM-1 [ 92 ].…”

“…Pg also inhibits EC proliferation [ 76 ], promotes EC apoptosis [ 75 , 76 , 77 , 78 ], epithelial–mesenchymal transition [ 65 ], oxidative stress, and inflammatory factor secretion [ 46 , 81 , 82 ], ultimately disrupting the vascular endothelial barrier. Under Pg stimulation, macrophages produce more inflammatory mediators [ 92 ], leading to increased lipid deposition [ 93 , 94 , 95 , 96 , 97 , 98 , 99 ] and exacerbating the inflammatory environment within the plaque. Pg promotes proliferation [ 103 , 107 ], phenotypic transformation [ 100 , 106 , 107 ], and calcification [ 104 ] of VSMCs.…”