Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease: A mechanistic link between local and systemic inflammation

Ying Gu, Hsi Ming Lee, Timo Sorsa, Aino Salminen, Maria E. Ryan, Marvin J Slepian, Lorne M. Golub

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)573-579
Number of pages7
JournalPharmacological Research
Volume64
Issue number6
DOIs
StatePublished - Dec 2011

Fingerprint

Tetracyclines
Periodontitis
Cardiovascular Diseases
Inflammation
Doxycycline
Apolipoprotein A-I
Acute Coronary Syndrome
Matrix Metalloproteinases
Interleukin-6
Mouth Diseases
Chronic Disease
Cytokines
Matrix Metalloproteinase 9
Periodontal Diseases
Tetracycline
Endotoxins
C-Reactive Protein
LDL Cholesterol
HDL Cholesterol
Peptide Hydrolases

Keywords

  • Cardiovascular disease
  • Chronic periodontitis
  • Inflammatory biomarkers
  • Tetracyclines

ASJC Scopus subject areas

  • Pharmacology

Cite this

Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease : A mechanistic link between local and systemic inflammation. / Gu, Ying; Lee, Hsi Ming; Sorsa, Timo; Salminen, Aino; Ryan, Maria E.; Slepian, Marvin J; Golub, Lorne M.

In: Pharmacological Research, Vol. 64, No. 6, 12.2011, p. 573-579.

Research output: Contribution to journalArticle

@article{3a2ec4ce8fd54438a7de081b31114abd,
title = "Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease: A mechanistic link between local and systemic inflammation",
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 = "Cardiovascular disease, Chronic periodontitis, Inflammatory biomarkers, Tetracyclines",
author = "Ying Gu and Lee, {Hsi Ming} and Timo Sorsa and Aino Salminen and Ryan, {Maria E.} and Slepian, {Marvin J} and Golub, {Lorne M.}",
year = "2011",
month = "12",
doi = "10.1016/j.phrs.2011.06.023",
language = "English (US)",
volume = "64",
pages = "573--579",
journal = "Pharmacological Research",
issn = "1043-6618",
publisher = "Academic Press Inc.",
number = "6",

}

TY - JOUR

T1 - Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease

T2 - A mechanistic link between local and systemic inflammation

AU - Gu, Ying

AU - Lee, Hsi Ming

AU - Sorsa, Timo

AU - Salminen, Aino

AU - Ryan, Maria E.

AU - Slepian, Marvin J

AU - Golub, Lorne M.

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

KW - Cardiovascular disease

KW - Chronic periodontitis

KW - Inflammatory biomarkers

KW - Tetracyclines

UR - http://www.scopus.com/inward/record.url?scp=80054095409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80054095409&partnerID=8YFLogxK

U2 - 10.1016/j.phrs.2011.06.023

DO - 10.1016/j.phrs.2011.06.023

M3 - Article

C2 - 21771657

AN - SCOPUS:80054095409

VL - 64

SP - 573

EP - 579

JO - Pharmacological Research

JF - Pharmacological Research

SN - 1043-6618

IS - 6

ER -