Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells

被引:512
作者
Marx, N
Schönbeck, U
Lazar, MA
Libby, P
Plutzky, J
机构
[1] Harvard Univ, Div Cardiovasc, Vasc Med & Atherosclerosis Unit, Brigham & Womens Hosp,Med Sch,Dept Med, Boston, MA 02115 USA
[2] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Dept Med, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA
关键词
gene expression; vascular smooth muscle cell; migration; peroxisome proliferator-activated receptor gamma; troglitazone;
D O I
10.1161/01.RES.83.11.1097
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mi,oration. 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-(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 gelatinolytic activity in the supernatants in a concentration-dependent manner. Six different PPAR alpha activators lacked such effects. Addition of prostaglandin F-2 alpha, known to limit PPAR gamma activity, diminished the MMP-9 inhibition seen with either troglitazone or 15d-PGJ(2), further implicating PPAR gamma in these effects. Finally, troglitazone and 15d-PGJ(2) inhibited the platelet-derived growth factor-BE-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.
引用
收藏
页码:1097 / 1103
页数:7
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