Goetze S, Xi X P, Kawano H, Gotlibowski T, Fleck E, Hsueh W A, Law R E
University of California, Los Angeles, School of Medicine, Division of Endocrinology 90095, USA.
J Cardiovasc Pharmacol. 1999 May;33(5):798-806. doi: 10.1097/00005344-199905000-00018.
The purpose of this study was to determine the effect of the peroxisome proliferator-activated receptor gamma-(PPAR gamma) ligands troglitazone (TRO), rosiglitazone (RSG), and 15-deoxy-delta prostaglandin J2 (15d-PGJ2) on vascular smooth muscle cell (VSMC) migration directed by multiple chemoattractants. Involvement of mitogen-activated protein kinase (MAPK) in migration also was examined, because TRO was previously shown to inhibit nuclear events stimulated by this pathway during mitogenic signaling in VSMCs. Migration of rat aortic VSMCs was induced 5.4-fold by PDGF, 4.6-fold by thrombin, and 2.3-fold by insulin-like growth factor I (IGF-I; all values of p < 0.05). The PPAR gamma ligands 15d-PGJ2, RSG, or TRO all inhibited VSMC migration with the following order of potency: 15d-PGJ2 > RSG > TRO. Inhibition of MAPK signaling with PD98059 completely blocked PDGF-, thrombin-, and IGF-I-induced migration. All chemoattractants induced MAPK activation. PPAR gamma ligands did not inhibit MAPK activation, suggesting a nuclear effect of these ligands downstream of MAPK. The importance of nuclear events was confirmed because actinomycin D also blocked migration. We conclude that PPAR gamma ligands are potent inhibitors of VSMC migration pathways, dependent on MAPK and nuclear events. PPAR gamma ligands act downstream of the cytoplasmic activation of MAPK and appear to exert their effects in the nucleus. Because VSMC migration plays an important role in the formation of atherosclerotic lesions and restenosis, PPAR gamma ligands like TRO and RSG, which ameliorate insulin resistance in humans, also may protect the vasculature from diabetes-enhanced injury.
本研究的目的是确定过氧化物酶体增殖物激活受体γ（PPARγ）配体曲格列酮（TRO）、罗格列酮（RSG）和15-脱氧-δ-前列腺素J2（15d-PGJ2）对多种趋化因子介导的血管平滑肌细胞（VSMC）迁移的影响。还研究了丝裂原活化蛋白激酶（MAPK）在迁移中的作用，因为先前已表明TRO在VSMC的有丝分裂信号传导过程中可抑制该途径刺激的核事件。血小板衍生生长因子（PDGF）可使大鼠主动脉VSMC的迁移诱导增加5.4倍，凝血酶可使其增加4.6倍，胰岛素样生长因子I（IGF-I）可使其增加2.3倍（所有p值均<0.05）。PPARγ配体15d-PGJ2、RSG或TRO均抑制VSMC迁移，其效力顺序如下：15d-PGJ2>RSG>TRO。用PD98059抑制MAPK信号传导可完全阻断PDGF、凝血酶和IGF-I诱导的迁移。所有趋化因子均诱导MAPK活化。PPARγ配体不抑制MAPK活化，提示这些配体在MAPK下游具有核效应。放线菌素D也可阻断迁移，这证实了核事件的重要性。我们得出结论，PPARγ配体是VSMC迁移途径的有效抑制剂，依赖于MAPK和核事件。PPARγ配体在MAPK的细胞质活化下游起作用，并且似乎在细胞核中发挥其作用。由于VSMC迁移在动脉粥样硬化病变和再狭窄的形成中起重要作用，像TRO和RSG这样可改善人类胰岛素抵抗的PPARγ配体也可能保护血管系统免受糖尿病加重的损伤。
