Endothelin-1-mediated signaling in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in astrocytes

Shaoqing He, Ganesh Prasanna, Thomas Yorio

Research output: Contribution to journalArticleResearchpeer-review

54 Citations (Scopus)

Abstract

PURPOSE. Endothelin (ET)-1 levels are increased in aqueous and vitreous humor in patients with glaucoma and animal models of glaucoma. Whether the elevated ET-1 induces extracellular matrix (ECM) remodeling in the optic nerve head is still unknown. In the present study, the regulation of matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases (MMPs/TIMPs) and ECM remodeling in ET-1-activated human optic nerve head astrocytes (hONAs) were determined. METHODS. Primary hONAs were exposed to ET-1 for 1 day and 4 days. Incubation media were subjected to zymography and Western blot to detect activity and expression of MMPs and TIMPs. Fibronectin (FN) was monitored by Western blot and immunofluorescent staining. RESULTS. ET-1 increased the activity of MMP-2 and the expression of TIMP-1 and -2 in hONAs. The expression of TIMP-1 and -2 induced by ET-1 was abolished by application of inhibitors of mitogen-activated protein kinase (MAPK) or PKC, leading to enhanced activity of MMP-2. Knockdown of MMP-2, by using small interfering (si)RNA, not only decreased the activity of MMP-2 but also decreased the expression of TIMP-1 and -2. ET-1 increased the soluble (s)FN expression as well as FN matrix formation. However, the accumulation of sFN did not enhance FN matrix formation. Unlike ET-1's effects on MMP-2, blockade of MAPK and PKC did not alter the expression and deposition pattern of FN in hONAs. CONCLUSIONS. ET-1 increased the expression and activity of MMP-2 and TIMP-1 and -2. The ERK-MAPK and PKC pathways are involved in the regulation of expression of MMP-2 and TIMP-1 and -2. ET-1's effects on MMPs/TIMPs may be important, not only in regulating the expression of MMPs and TIMPs, but also in influencing ECM remodeling.

Original languageEnglish
Pages (from-to)3737-3745
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number8
DOIs
StatePublished - 1 Aug 2007

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Tissue Inhibitor of Metalloproteinases
Matrix Metalloproteinase Inhibitors
Endothelin-1
Matrix Metalloproteinases
Astrocytes
Tissue Inhibitor of Metalloproteinase-2
Tissue Inhibitor of Metalloproteinase-1
Optic Disk
Fibronectins
Extracellular Matrix
Mitogen-Activated Protein Kinases
Glaucoma
Western Blotting
Vitreous Body
Aqueous Humor
Mitogen-Activated Protein Kinase 1
Small Interfering RNA
Animal Models

Cite this

@article{fc761699608f44c19303aef412c4be7d,
title = "Endothelin-1-mediated signaling in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in astrocytes",
abstract = "PURPOSE. Endothelin (ET)-1 levels are increased in aqueous and vitreous humor in patients with glaucoma and animal models of glaucoma. Whether the elevated ET-1 induces extracellular matrix (ECM) remodeling in the optic nerve head is still unknown. In the present study, the regulation of matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases (MMPs/TIMPs) and ECM remodeling in ET-1-activated human optic nerve head astrocytes (hONAs) were determined. METHODS. Primary hONAs were exposed to ET-1 for 1 day and 4 days. Incubation media were subjected to zymography and Western blot to detect activity and expression of MMPs and TIMPs. Fibronectin (FN) was monitored by Western blot and immunofluorescent staining. RESULTS. ET-1 increased the activity of MMP-2 and the expression of TIMP-1 and -2 in hONAs. The expression of TIMP-1 and -2 induced by ET-1 was abolished by application of inhibitors of mitogen-activated protein kinase (MAPK) or PKC, leading to enhanced activity of MMP-2. Knockdown of MMP-2, by using small interfering (si)RNA, not only decreased the activity of MMP-2 but also decreased the expression of TIMP-1 and -2. ET-1 increased the soluble (s)FN expression as well as FN matrix formation. However, the accumulation of sFN did not enhance FN matrix formation. Unlike ET-1's effects on MMP-2, blockade of MAPK and PKC did not alter the expression and deposition pattern of FN in hONAs. CONCLUSIONS. ET-1 increased the expression and activity of MMP-2 and TIMP-1 and -2. The ERK-MAPK and PKC pathways are involved in the regulation of expression of MMP-2 and TIMP-1 and -2. ET-1's effects on MMPs/TIMPs may be important, not only in regulating the expression of MMPs and TIMPs, but also in influencing ECM remodeling.",
author = "Shaoqing He and Ganesh Prasanna and Thomas Yorio",
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Endothelin-1-mediated signaling in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in astrocytes. / He, Shaoqing; Prasanna, Ganesh; Yorio, Thomas.

In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 8, 01.08.2007, p. 3737-3745.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Endothelin-1-mediated signaling in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in astrocytes

AU - He, Shaoqing

AU - Prasanna, Ganesh

AU - Yorio, Thomas

PY - 2007/8/1

Y1 - 2007/8/1

N2 - PURPOSE. Endothelin (ET)-1 levels are increased in aqueous and vitreous humor in patients with glaucoma and animal models of glaucoma. Whether the elevated ET-1 induces extracellular matrix (ECM) remodeling in the optic nerve head is still unknown. In the present study, the regulation of matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases (MMPs/TIMPs) and ECM remodeling in ET-1-activated human optic nerve head astrocytes (hONAs) were determined. METHODS. Primary hONAs were exposed to ET-1 for 1 day and 4 days. Incubation media were subjected to zymography and Western blot to detect activity and expression of MMPs and TIMPs. Fibronectin (FN) was monitored by Western blot and immunofluorescent staining. RESULTS. ET-1 increased the activity of MMP-2 and the expression of TIMP-1 and -2 in hONAs. The expression of TIMP-1 and -2 induced by ET-1 was abolished by application of inhibitors of mitogen-activated protein kinase (MAPK) or PKC, leading to enhanced activity of MMP-2. Knockdown of MMP-2, by using small interfering (si)RNA, not only decreased the activity of MMP-2 but also decreased the expression of TIMP-1 and -2. ET-1 increased the soluble (s)FN expression as well as FN matrix formation. However, the accumulation of sFN did not enhance FN matrix formation. Unlike ET-1's effects on MMP-2, blockade of MAPK and PKC did not alter the expression and deposition pattern of FN in hONAs. CONCLUSIONS. ET-1 increased the expression and activity of MMP-2 and TIMP-1 and -2. The ERK-MAPK and PKC pathways are involved in the regulation of expression of MMP-2 and TIMP-1 and -2. ET-1's effects on MMPs/TIMPs may be important, not only in regulating the expression of MMPs and TIMPs, but also in influencing ECM remodeling.

AB - PURPOSE. Endothelin (ET)-1 levels are increased in aqueous and vitreous humor in patients with glaucoma and animal models of glaucoma. Whether the elevated ET-1 induces extracellular matrix (ECM) remodeling in the optic nerve head is still unknown. In the present study, the regulation of matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases (MMPs/TIMPs) and ECM remodeling in ET-1-activated human optic nerve head astrocytes (hONAs) were determined. METHODS. Primary hONAs were exposed to ET-1 for 1 day and 4 days. Incubation media were subjected to zymography and Western blot to detect activity and expression of MMPs and TIMPs. Fibronectin (FN) was monitored by Western blot and immunofluorescent staining. RESULTS. ET-1 increased the activity of MMP-2 and the expression of TIMP-1 and -2 in hONAs. The expression of TIMP-1 and -2 induced by ET-1 was abolished by application of inhibitors of mitogen-activated protein kinase (MAPK) or PKC, leading to enhanced activity of MMP-2. Knockdown of MMP-2, by using small interfering (si)RNA, not only decreased the activity of MMP-2 but also decreased the expression of TIMP-1 and -2. ET-1 increased the soluble (s)FN expression as well as FN matrix formation. However, the accumulation of sFN did not enhance FN matrix formation. Unlike ET-1's effects on MMP-2, blockade of MAPK and PKC did not alter the expression and deposition pattern of FN in hONAs. CONCLUSIONS. ET-1 increased the expression and activity of MMP-2 and TIMP-1 and -2. The ERK-MAPK and PKC pathways are involved in the regulation of expression of MMP-2 and TIMP-1 and -2. ET-1's effects on MMPs/TIMPs may be important, not only in regulating the expression of MMPs and TIMPs, but also in influencing ECM remodeling.

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U2 - 10.1167/iovs.06-1138

DO - 10.1167/iovs.06-1138

M3 - Article

VL - 48

SP - 3737

EP - 3745

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 8

ER -