Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells.
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.
Marx
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Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Schönbeck
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Lazar
M A
MA
Libby
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P
Plutzky
J
J
D000077214:Becaplermin; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics; D015237:Dinoprost / Q000494:pharmacology; D005780:Gelatin / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D020780:Matrix Metalloproteinase 9; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077214:Becaplermin; D005780:Gelatin; D015237:Dinoprost; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; D000077288:Troglitazone; D015230:Prostaglandin D2