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 r ole in atherogenesis and restenosis after arterial interventions. The expression of matrix metalloproteinases (MMPs), particularly MMP-9, co ntributes to VSMC mi,oration. This process requires degradation of bas al laminae and other components of the arterial extracellular matrix. Peroxisome proliferator-activated receptors (PPARs), members of the nu clear receptor family, regulate gene expression after activation by va rious ligands. Recent studies have suggested opposing effects of PPAR gamma (PPAR gamma) activation on atherogenesis. The present study test ed 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 al pha and PPAR gamma mRNA and protein. Treatment of VSMCs with the PPAR gamma ligands troglitazone and the naturally occurring 15-deoxy-(Delta 12,14)-prostaglandin J(2) (15d-PGJ(2)) decreased phorbol 12-myristate 13-acetate-induced MMP-9 mRNA and protein levels, as well as MMP-9 ge latinolytic activity in the supernatants in a concentration-dependent manner. Six different PPAR alpha activators lacked such effects. Addit ion of prostaglandin F-2 alpha, known to limit PPAR gamma activity, di minished the MMP-9 inhibition seen with either troglitazone or 15d-PGJ (2), further implicating PPAR gamma in these effects. Finally, troglit azone and 15d-PGJ(2) inhibited the platelet-derived growth factor-BE-i nduced 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 anti diabetic agent troglitazone or naturally occurring ligands, may act to counterbalance other potentially proatherosclerotic PPAR gamma effect s.