Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells
Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells
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DOI：
10.1161/01.res.83.11.1097
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发表时间：
1998-11-30
影响因子：
20.1
通讯作者：
Plutzky, J
中科院分区：
文献类型：
--
作者：
Marx, N;Schönbeck, U;Plutzky, J
血管平滑肌细胞（VSMCs）的迁移在动脉介入后动脉粥样硬化和再狭窄中起重要作用。基质金属蛋白酶（MMPs）的表达，特别是MMP-9的表达与VSMC的发生有关。这个过程需要基底膜和动脉细胞外基质的其他成分的降解。过氧化物酶体增殖物激活受体（PPARs）是核受体家族的成员，在各种配体激活后调节基因表达。最近的研究表明，PPAR γ (PPAR γ)激活对动脉粥样硬化的相反作用。本研究验证了人类VSMCs表达PPAR α (PPAR α)和PPAR γ的假设，以及VSMCs中PPAR激动剂调节MMP-9的表达和活性以及VSMC迁移的假设。人VSMCs表达PPAR α和PPAR γ mRNA和蛋白。用PPAR γ配体曲格列酮和天然存在的15-脱氧-(δ 12,14)-前列腺素J(2) （15d-PGJ(2)）治疗VSMCs，降低了phorbol 12-肉豆酸酯13-乙酸酯诱导的MMP-9 mRNA和蛋白水平，以及上清液中MMP-9的溶胶活性，并呈浓度依赖性。六种不同的PPAR α激活剂没有这种效果。已知能限制PPAR γ活性的前列腺素F-2 α的加入，降低了曲格列酮或15d-PGJ对MMP-9的抑制作用(2)，进一步表明PPAR γ参与了这些作用。最后，曲格列酮和15d-PGJ(2)在体外以浓度依赖的方式抑制血小板源性生长因子be诱导的VSMCs迁移。PPAR γ激活可能调节VSMC迁移和MMP-9的表达和活性。因此，通过抗糖尿病药物曲格列酮或天然存在的配体，VSMCs中的PPAR γ激活可能会抵消其他潜在的促动脉粥样硬化PPAR γ效应。
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.