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

• Published in: Circulation research Vol. 83; no. 11; pp. 1097 - 1103
• Main Authors: Marx, Nikolaus, Schonbeck, Uwe, Lazar, Mitchell A, Libby, Peter, Plutzky, Jorge
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 30.11.1998; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Becaplermin; Biological and medical sciences; Blood vessels and receptors; Cell Movement - drug effects; Cells, Cultured - drug effects; Chromans - pharmacology; Collagenases - biosynthesis; Collagenases - genetics; Dinoprost - pharmacology; Fundamental and applied biological sciences. Psychology; Gelatin - metabolism; Gene Expression - drug effects; Humans; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - metabolism; Platelet-Derived Growth Factor - antagonists & inhibitors; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; Proto-Oncogene Proteins c-sis; Receptors, Cytoplasmic and Nuclear - biosynthesis; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - physiology; RNA, Messenger - biosynthesis; Thiazoles - pharmacology; Thiazolidinediones; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription Factors - physiology; Troglitazone; Vertebrates: cardiovascular system; Human; Nuclear receptor; Enzyme; Migration; Metalloendopeptidases; Smooth muscle; Gene expression; Gelatinase B; Peroxisome proliferator; Peptidases; Activator; Saphenous vein; Blood vessel; Hydrolases; Circulatory system; Transcription factor
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.res.83.11.1097

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 (PPAR gamma) activation on atherogenesis. The present study tested the hypotheses that human VSMCs express PPAR alpha (PPAR alpha) and PPAR gamma and that PPAR agonists in VSMCs modulate MMP-9 expression and activity, as well as VSMC migration. Human VSMCs expressed PPAR alpha and PPAR gamma mRNA and protein. Treatment of VSMCs with the PPAR gamma ligands troglitazone and the naturally occurring 15-deoxy- 12,14 -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 PPAR alpha activators lacked such effects. Addition of prostaglandin F2 alpha, known to limit PPAR gamma activity, diminished the MMP-9 inhibition seen with either troglitazone or 15d-PGJ2, further implicating PPAR gamma 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. PPAR gamma activation may regulate VSMC migration and expression and activity of MMP-9. Thus, PPAR gamma activation in VSMCs, via the antidiabetic agent troglitazone or naturally occurring ligands, may act to counterbalance other potentially proatherosclerotic PPAR gamma effects. (Circ Res. 1998;83:1097-1103.)