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Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular
N Marx1, U Schönbeck, M A Lazar
1Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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 (PPARgamma) activation on atherogenesis. The present study tested the hypotheses that human VSMCs express PPAR alpha (PPARalpha) and PPARgamma and that PPAR agonists in VSMCs modulate MMP-9 expression and activity, as well as VSMC migration. Human VSMCs expressed PPARalpha and PPARgamma mRNA and protein. Treatment of VSMCs with the PPARgamma ligands troglitazone and the naturally occurring 15-deoxy-Delta12, 14-prostaglandin J2 (15d-PGJ2) 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 PPARalpha activators lacked such effects. Addition of prostaglandin F2alpha, known to limit PPARgamma activity, diminished the MMP-9 inhibition seen with either troglitazone or 15d-PGJ2, further implicating PPARgamma in these effects. Finally, troglitazone and 15d-PGJ2 inhibited the platelet-derived growth factor-BB-induced migration of VSMCs in vitro in a concentration-dependent manner. PPARgamma activation may regulate VSMC migration and expression and activity of MMP-9. Thus, PPARgamma activation in VSMCs, via the antidiabetic agent troglitazone or naturally occurring ligands, may act to counterbalance other potentially proatherosclerotic PPARgamma effects.
Insights
Peroxisome proliferator-activated receptor gamma (PPARgamma) activation in vascular smooth muscle cells (VSMCs) inhibits matrix metalloproteinase-9 (MMP-9) and cell migration. This suggests PPARgamma agonists may counteract proatherosclerotic effects.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Endocrinology
Background:
- Vascular smooth muscle cell (VSMC) migration is crucial in atherosclerosis and restenosis.
- Matrix metalloproteinase-9 (MMP-9) expression and activity drive VSMC migration by degrading extracellular matrix.
- Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating gene expression; PPAR gamma (PPARgamma) has shown conflicting roles in atherogenesis.
Purpose of the Study:
- To investigate if human VSMCs express PPAR alpha (PPARalpha) and PPARgamma.
- To determine if PPAR agonists modulate MMP-9 expression, activity, and VSMC migration.
- To elucidate the role of PPARgamma in regulating these processes.
Main Methods:
- Human VSMCs were analyzed for PPARalpha and PPARgamma mRNA and protein expression.
- VSMCs were treated with PPARgamma ligands (troglitazone, 15d-PGJ2) and PPARalpha activators.
- MMP-9 expression, activity, and VSMC migration induced by growth factors were assessed.
Main Results:
- Human VSMCs express both PPARalpha and PPARgamma.
- PPARgamma activation by troglitazone and 15d-PGJ2 significantly reduced MMP-9 mRNA, protein, and activity.
- PPARgamma agonists also inhibited platelet-derived growth factor-BB-induced VSMC migration.
Conclusions:
- PPARgamma activation in VSMCs regulates MMP-9 expression and activity, thereby influencing VSMC migration.
- PPARgamma agonists like troglitazone may offer a therapeutic strategy to counterbalance proatherosclerotic effects.
- These findings highlight a potential protective role for PPARgamma in vascular disease.