Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease: A mechanistic link between local and systemic inflammation |
| |
Authors: | Ying Gu Hsi-Ming Lee Timo Sorsa Aino Salminen Maria E. Ryan Marvin J. Slepian Lorne M. Golub |
| |
Affiliation: | aDepartment of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, United States;bDepartment of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY 11794, United States;cDepartment of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Institute of Dentistry, University of Helsinki, Helsinki, Finland;dSarver Heart Center, University of Arizona, Tucson, AZ 85724, United States |
| |
Abstract: | Periodontitis, one of the most common chronic inflammatory diseases afflicting man, is increasingly being recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Non-antimicrobial tetracyclines are known to have inhibitory effects on inflammatory mediators and effector molecules, including cytokines and matrix metalloproteinases (MMPs), associated with both diseases. In this paper, we discuss the evidence that doxycycline and related non-antibiotic chemically modified tetracyclines (e.g., CMT-3) can effectively reduce cytokine (TNF-α, IL-6, and MCP-1) production by human mononuclear inflammatory cells when stimulated either by endotoxin (LPS) or by a complex of C-reactive protein/oxidized LDL cholesterol relevant to the pathogenesis of periodontal disease and ASCVD, respectively. This inhibition by tetracycline compounds appears to be mediated at least in part by a suppression of the phosphorylation/activation of the NFκB cell signaling pathway. We are currently conducting clinical trials on patients who exhibit both diseases, and our preliminary data suggest that virtually all acute coronary syndrome (ACS) patients exhibit moderate-to-severe periodontitis, a higher incidence of this oral inflammatory disease than that seen in the population at large. In other studies, a non-antimicrobial formulation of doxycycline (SDD) has been found to dramatically reduce hsCRP, IL-6 and MMP-9 levels in plasma of ACS patients, and SDD has also been found to significantly increase serum levels of both cardio-protective HDL cholesterol and its core molecule apolipoprotein A-I in ASCVD-vulnerable patients with periodontitis. Our current research suggests that one mechanism involved may be the ability of SDD to inhibit MMP-mediated HDL loss by protecting apolipoprotein A-I from proteinase attack. These pleiotropic mechanisms of non-antimicrobial tetracyclines provide significant therapeutic potential to treat chronic inflammatory diseases including both periodontitis and ASCVD. |
| |
Keywords: | Abbreviations: ACS, acute coronary syndrome AMI, acute myocardial infarction Apo, apolipoprotein ASCVD, atherosclerotic cardiovascular disease CMT, chemically modified tetracycline CP, chronic periodontitis CRP, C-reactive protein GCF, gingival crevicular fluid HDL, high density lipoprotein IL, interleukin LPS, lipopolysaccharide/endotoxin LDL, low density lipoprotein MCP, macrophage chemoattractant protein MMP, matrix metalloproteinase MI, myocardial infarction NO, nitric oxide PLA2, phospholipase A2 PD, pocket depth PGE2, prostaglandin E2 SDD, sub-antimicrobial dose doxycycline TC, tetracycline TNF, tumor necrosis factor |
本文献已被 ScienceDirect 等数据库收录! |
|