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.