DOI: 10.1161/01.res.83.11.1097. Peroxisome Proliferator-Activated Receptor Gamma Activators Inhibit Gene Expression and Migration in Human Vascular Smooth Muscle Cells [Penn]

Peroxisome Proliferator-Activated Receptor Gamma Activators Inhibit Gene Expression and Migration in Human Vascular Smooth Muscle Cells

10.1161/01.res.83.11.1097

Crossref journal-article

Ovid Technologies (Wolters Kluwer Health)

Circulation Research (276)

Abstract

Abstract —Migration of vascular smooth muscle cells (VSMCs) plays an important role in atherogenesis and restenosis after arterial interventions. The expression of matrix metalloproteinases (MMPs), particularly MMP-9, contributes to VSMC migration. This process requires degradation of basal laminae and other components of the arterial extracellular matrix. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor family, regulate gene expression after activation by various ligands. Recent studies have suggested opposing effects of PPAR gamma (PPARγ) activation on atherogenesis. The present study tested the hypotheses that human VSMCs express PPAR alpha (PPARα) and PPARγ and that PPAR agonists in VSMCs modulate MMP-9 expression and activity, as well as VSMC migration. Human VSMCs expressed PPARα and PPARγ mRNA and protein. Treatment of VSMCs with the PPARγ ligands troglitazone and the naturally occurring 15-deoxy- Δ12,14 -prostaglandin J 2 (15d-PGJ 2 ) decreased phorbol 12-myristate 13-acetate–induced MMP-9 mRNA and protein levels, as well as MMP-9 gelatinolytic activity in the supernatants in a concentration-dependent manner. Six different PPARα activators lacked such effects. Addition of prostaglandin F 2α , known to limit PPARγ activity, diminished the MMP-9 inhibition seen with either troglitazone or 15d-PGJ 2 , further implicating PPARγ in these effects. Finally, troglitazone and 15d-PGJ 2 inhibited the platelet-derived growth factor-BB–induced migration of VSMCs in vitro in a concentration-dependent manner. PPARγ activation may regulate VSMC migration and expression and activity of MMP-9. Thus, PPARγ activation in VSMCs, via the antidiabetic agent troglitazone or naturally occurring ligands, may act to counterbalance other potentially proatherosclerotic PPARγ effects.

Bibliography

Marx, N., SchoÌnbeck, U., Lazar, M. A., Libby, P., & Plutzky, J. (1998). Peroxisome Proliferator-Activated Receptor Gamma Activators Inhibit Gene Expression and Migration in Human Vascular Smooth Muscle Cells. Circulation Research, 83(11), 1097â1103.

Authors 5

Nikolaus Marx (first)
Uwe Schönbeck (additional)
Mitchell A. Lazar (additional)
Peter Libby (additional)
Jorge Plutzky (additional)

References 34 Referenced 398

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10.1016/S0021-9258(18)47383-8
10.1210/mend-4-10-1522
Pfahl M. Nuclear receptor/AP-1 interaction. Endocr Rev. 1993;14:651–658. / Endocr Rev (1993)
10.1128/MCB.17.3.1552
10.1016/S0092-8674(00)81118-6
Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after arterial injury, I: smooth muscle growth in the absence of endothelium. Lab Invest. 1983;49:327–333. / Lab Invest (1983)
10.2337/diab.47.1.130
10.1210/jcem.83.3.4668-1
10.1056/NEJM199803263381302
10.1056/NEJM199803263381303

Dates

Type	When
Created	13 years, 2 months ago (June 11, 2012, 8:47 p.m.)
Deposited	1 year, 3 months ago (May 12, 2024, 4:23 p.m.)
Indexed	1 week, 2 days ago (Aug. 28, 2025, 8:53 a.m.)
Issued	26 years, 9 months ago (Nov. 30, 1998)
Published	26 years, 9 months ago (Nov. 30, 1998)
Published Print	26 years, 9 months ago (Nov. 30, 1998)

Funders 0

None

BibTeX

@article{Marx_1998, title={Peroxisome Proliferator-Activated Receptor Gamma Activators Inhibit Gene Expression and Migration in Human Vascular Smooth Muscle Cells}, volume={83}, ISSN={1524-4571}, url={http://dx.doi.org/10.1161/01.res.83.11.1097}, DOI={10.1161/01.res.83.11.1097}, number={11}, journal={Circulation Research}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Marx, Nikolaus and Schönbeck, Uwe and Lazar, Mitchell A. and Libby, Peter and Plutzky, Jorge}, year={1998}, month=nov, pages={1097–1103} }

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  "abstract": "<jats:p>\n            <jats:italic>Abstract</jats:italic>\n            \u2014Migration of vascular smooth muscle cells (VSMCs) plays an important role in atherogenesis and restenosis after arterial interventions. The expression of matrix metalloproteinases (MMPs), particularly MMP-9, contributes to VSMC migration. This process requires degradation of basal laminae and other components of the arterial extracellular matrix. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor family, regulate gene expression after activation by various ligands. Recent studies have suggested opposing effects of PPAR gamma (PPAR\u03b3) activation on atherogenesis. The present study tested the hypotheses that human VSMCs express PPAR alpha (PPAR\u03b1) and PPAR\u03b3 and that PPAR agonists in VSMCs modulate MMP-9 expression and activity, as well as VSMC migration. Human VSMCs expressed PPAR\u03b1 and PPAR\u03b3 mRNA and protein. Treatment of VSMCs with the PPAR\u03b3 ligands troglitazone and the naturally occurring 15-deoxy-\n            <jats:sup>\u039412,14</jats:sup>\n            -prostaglandin J\n            <jats:sub>2</jats:sub>\n            (15d-PGJ\n            <jats:sub>2</jats:sub>\n            ) decreased phorbol 12-myristate 13-acetate\u2013induced MMP-9 mRNA and protein levels, as well as MMP-9 gelatinolytic activity in the supernatants in a concentration-dependent manner. Six different PPAR\u03b1 activators lacked such effects. Addition of prostaglandin F\n            <jats:sub>2\u03b1</jats:sub>\n            , known to limit PPAR\u03b3 activity, diminished the MMP-9 inhibition seen with either troglitazone or 15d-PGJ\n            <jats:sub>2</jats:sub>\n            , further implicating PPAR\u03b3 in these effects. Finally, troglitazone and 15d-PGJ\n            <jats:sub>2</jats:sub>\n            inhibited the platelet-derived growth factor-BB\u2013induced migration of VSMCs in vitro in a concentration-dependent manner. PPAR\u03b3 activation may regulate VSMC migration and expression and activity of MMP-9. Thus, PPAR\u03b3 activation in VSMCs, via the antidiabetic agent troglitazone or naturally occurring ligands, may act to counterbalance other potentially proatherosclerotic PPAR\u03b3 effects.\n          </jats:p>",
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