Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells

Jian Liu, Wanfen Xiong, Lisa Baca-Regen, Hideaki Nagase, Bernard Timothy Baxter

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Degradation of the extracellular matrix components elastin and collagen has been implicated in vascular diseases, including abdominal aortic aneurysm (AAA) and atherosclerotic plaque rupture. Increased expression of matrix metalloproteinases (MMPs) is involved in these disease processes. Our previous studies have demonstrated that MMP-2 derived from mesenchymal cells is required for aneurysm development in a murine model. Doxycycline is a nonspecific inhibitor of MMPs. In the present study, the mechanisms of the inhibitory effects of doxycycline on MMP-2 expression from cultured human aortic smooth muscle cells (SMCs) and human aortic aneurysm tissue explants were studied. Doxycycline inhibited MMP-2 expression from cultured SMCs in a concentration-dependent manner (5-40 μg/mL; inhibitory concentration of 50%, 6.5 μg/mL). At normal therapeutic serum concentration (5 μg/mL) doxycycline significantly reduced MMP-2 production from SMCs (37%; P <.05), which were stimulated with conditioned media from macrophage or lymphocyte co-culture simulating the inflammatory milieu of AAA tissue. This correlated with a decrease in MMP-2 mRNA half-life, from 49 hours to 28 hours, which suggests that doxycycline inhibits SMC MMP-2 production in part by reducing MMP-2 mRNA stability. When AAA tissue was cultured for 10 days with doxycycline at concentrations of 2.5 to 40 μg/mL, the media exhibited a concentration-dependent decrease in both active and latent forms of MMP-2 and MMP-9. Doxycycline at a concentration of 5 μg/mL reduced active and latent MMP-2 secreted from cultured AAA tissue by 50% and 30%, respectively (P < .05). These study findings demonstrate that doxycycline at standard therapeutic serum concentrations inhibits MMP-2 expression from cultured human aortic SMCs and AAA tissue explants. Inasmuch as MMP activity contributes to extracellular matrix degradation in AAAs and atherosclerotic plaque, doxycycline may have potential value in treating these diseases.

Original languageEnglish (US)
Pages (from-to)1376-1383
Number of pages8
JournalJournal of vascular surgery
Volume38
Issue number6
DOIs
StatePublished - Dec 2003

Fingerprint

Doxycycline
Matrix Metalloproteinase 2
Smooth Muscle Myocytes
Abdominal Aortic Aneurysm
Atherosclerotic Plaques
Matrix Metalloproteinases
Extracellular Matrix
Matrix Metalloproteinase Inhibitors
Elastin
Aortic Aneurysm
Matrix Metalloproteinase 9
RNA Stability
Conditioned Culture Medium
Coculture Techniques
Serum
Vascular Diseases
Inhibitory Concentration 50
Aneurysm
Half-Life
Rupture

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Cite this

Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells. / Liu, Jian; Xiong, Wanfen; Baca-Regen, Lisa; Nagase, Hideaki; Baxter, Bernard Timothy.

In: Journal of vascular surgery, Vol. 38, No. 6, 12.2003, p. 1376-1383.

Research output: Contribution to journalArticle

@article{ab44ef05f0b44431a94bce17eb19b131,
title = "Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells",
abstract = "Degradation of the extracellular matrix components elastin and collagen has been implicated in vascular diseases, including abdominal aortic aneurysm (AAA) and atherosclerotic plaque rupture. Increased expression of matrix metalloproteinases (MMPs) is involved in these disease processes. Our previous studies have demonstrated that MMP-2 derived from mesenchymal cells is required for aneurysm development in a murine model. Doxycycline is a nonspecific inhibitor of MMPs. In the present study, the mechanisms of the inhibitory effects of doxycycline on MMP-2 expression from cultured human aortic smooth muscle cells (SMCs) and human aortic aneurysm tissue explants were studied. Doxycycline inhibited MMP-2 expression from cultured SMCs in a concentration-dependent manner (5-40 μg/mL; inhibitory concentration of 50{\%}, 6.5 μg/mL). At normal therapeutic serum concentration (5 μg/mL) doxycycline significantly reduced MMP-2 production from SMCs (37{\%}; P <.05), which were stimulated with conditioned media from macrophage or lymphocyte co-culture simulating the inflammatory milieu of AAA tissue. This correlated with a decrease in MMP-2 mRNA half-life, from 49 hours to 28 hours, which suggests that doxycycline inhibits SMC MMP-2 production in part by reducing MMP-2 mRNA stability. When AAA tissue was cultured for 10 days with doxycycline at concentrations of 2.5 to 40 μg/mL, the media exhibited a concentration-dependent decrease in both active and latent forms of MMP-2 and MMP-9. Doxycycline at a concentration of 5 μg/mL reduced active and latent MMP-2 secreted from cultured AAA tissue by 50{\%} and 30{\%}, respectively (P < .05). These study findings demonstrate that doxycycline at standard therapeutic serum concentrations inhibits MMP-2 expression from cultured human aortic SMCs and AAA tissue explants. Inasmuch as MMP activity contributes to extracellular matrix degradation in AAAs and atherosclerotic plaque, doxycycline may have potential value in treating these diseases.",
author = "Jian Liu and Wanfen Xiong and Lisa Baca-Regen and Hideaki Nagase and Baxter, {Bernard Timothy}",
year = "2003",
month = "12",
doi = "10.1016/S0741-5214(03)01022-X",
language = "English (US)",
volume = "38",
pages = "1376--1383",
journal = "Journal of Vascular Surgery",
issn = "0741-5214",
publisher = "Mosby Inc.",
number = "6",

}

TY - JOUR

T1 - Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells

AU - Liu, Jian

AU - Xiong, Wanfen

AU - Baca-Regen, Lisa

AU - Nagase, Hideaki

AU - Baxter, Bernard Timothy

PY - 2003/12

Y1 - 2003/12

N2 - Degradation of the extracellular matrix components elastin and collagen has been implicated in vascular diseases, including abdominal aortic aneurysm (AAA) and atherosclerotic plaque rupture. Increased expression of matrix metalloproteinases (MMPs) is involved in these disease processes. Our previous studies have demonstrated that MMP-2 derived from mesenchymal cells is required for aneurysm development in a murine model. Doxycycline is a nonspecific inhibitor of MMPs. In the present study, the mechanisms of the inhibitory effects of doxycycline on MMP-2 expression from cultured human aortic smooth muscle cells (SMCs) and human aortic aneurysm tissue explants were studied. Doxycycline inhibited MMP-2 expression from cultured SMCs in a concentration-dependent manner (5-40 μg/mL; inhibitory concentration of 50%, 6.5 μg/mL). At normal therapeutic serum concentration (5 μg/mL) doxycycline significantly reduced MMP-2 production from SMCs (37%; P <.05), which were stimulated with conditioned media from macrophage or lymphocyte co-culture simulating the inflammatory milieu of AAA tissue. This correlated with a decrease in MMP-2 mRNA half-life, from 49 hours to 28 hours, which suggests that doxycycline inhibits SMC MMP-2 production in part by reducing MMP-2 mRNA stability. When AAA tissue was cultured for 10 days with doxycycline at concentrations of 2.5 to 40 μg/mL, the media exhibited a concentration-dependent decrease in both active and latent forms of MMP-2 and MMP-9. Doxycycline at a concentration of 5 μg/mL reduced active and latent MMP-2 secreted from cultured AAA tissue by 50% and 30%, respectively (P < .05). These study findings demonstrate that doxycycline at standard therapeutic serum concentrations inhibits MMP-2 expression from cultured human aortic SMCs and AAA tissue explants. Inasmuch as MMP activity contributes to extracellular matrix degradation in AAAs and atherosclerotic plaque, doxycycline may have potential value in treating these diseases.

AB - Degradation of the extracellular matrix components elastin and collagen has been implicated in vascular diseases, including abdominal aortic aneurysm (AAA) and atherosclerotic plaque rupture. Increased expression of matrix metalloproteinases (MMPs) is involved in these disease processes. Our previous studies have demonstrated that MMP-2 derived from mesenchymal cells is required for aneurysm development in a murine model. Doxycycline is a nonspecific inhibitor of MMPs. In the present study, the mechanisms of the inhibitory effects of doxycycline on MMP-2 expression from cultured human aortic smooth muscle cells (SMCs) and human aortic aneurysm tissue explants were studied. Doxycycline inhibited MMP-2 expression from cultured SMCs in a concentration-dependent manner (5-40 μg/mL; inhibitory concentration of 50%, 6.5 μg/mL). At normal therapeutic serum concentration (5 μg/mL) doxycycline significantly reduced MMP-2 production from SMCs (37%; P <.05), which were stimulated with conditioned media from macrophage or lymphocyte co-culture simulating the inflammatory milieu of AAA tissue. This correlated with a decrease in MMP-2 mRNA half-life, from 49 hours to 28 hours, which suggests that doxycycline inhibits SMC MMP-2 production in part by reducing MMP-2 mRNA stability. When AAA tissue was cultured for 10 days with doxycycline at concentrations of 2.5 to 40 μg/mL, the media exhibited a concentration-dependent decrease in both active and latent forms of MMP-2 and MMP-9. Doxycycline at a concentration of 5 μg/mL reduced active and latent MMP-2 secreted from cultured AAA tissue by 50% and 30%, respectively (P < .05). These study findings demonstrate that doxycycline at standard therapeutic serum concentrations inhibits MMP-2 expression from cultured human aortic SMCs and AAA tissue explants. Inasmuch as MMP activity contributes to extracellular matrix degradation in AAAs and atherosclerotic plaque, doxycycline may have potential value in treating these diseases.

UR - http://www.scopus.com/inward/record.url?scp=0345167810&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0345167810&partnerID=8YFLogxK

U2 - 10.1016/S0741-5214(03)01022-X

DO - 10.1016/S0741-5214(03)01022-X

M3 - Article

C2 - 14681644

AN - SCOPUS:0345167810

VL - 38

SP - 1376

EP - 1383

JO - Journal of Vascular Surgery

JF - Journal of Vascular Surgery

SN - 0741-5214

IS - 6

ER -