Peroxisome Proliferator-Activated Receptor δ Regulates Extracellular Matrix and Apoptosis of Vascular Smooth Muscle Cells Through the Activation of Transforming Growth Factor-β1/Smad3
Peroxisome Proliferator-Activated Receptor δ Regulates Extracellular Matrix and Apoptosis of Vascular Smooth Muscle Cells Through the Activation of Transforming Growth Factor-β1/Smad3
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DOI：
10.1161/circresaha.108.189159
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发表时间：
2009-07-02
影响因子：
20.1
通讯作者：
Seo, Han Geuk
中科院分区：
文献类型：
--
作者：
Kim, Hyo Jung;Kim, Min Young;Seo, Han Geuk
细胞外基质的稳态和血管平滑肌细胞（VSMC）的凋亡是调节动脉粥样硬化斑块稳定性的关键组成部分。在这里，我们证明过氧化物酶体增殖物激活受体（PPAR）δ通过转化生长因子-β1及其效应子Smad3调节细胞外基质的合成和降解。 PPAR δ 的激活强烈增强了 I 型和 III 型胶原蛋白、纤连蛋白、弹性蛋白和 TIMP-3（金属蛋白酶 3 的组织抑制剂）的表达，但不增强 TIMP-1、基质金属蛋白酶-2 或 -9 的表达。 PPAR δ 对 III 型胶原表达的影响受到 PPAR δ 和 Smad3 分别与 III 型胶原基因启动子中的直接重复序列 1 位点和 Smad 结合元件直接结合的双重调节。 PPAR δ 的激活减弱了氧化低密度脂蛋白诱导的 VSMC 中的细胞凋亡，并且在用外源 I 型和/或 III 型胶原处理细胞时观察到类似的抗凋亡作用。给小鼠施用 PPAR δ 配体 GW501516 也抑制了弹性蛋白酶诱导的主动脉 VSMC 细胞死亡。这些结果表明PPARδ诱导的细胞外基质蛋白上调发挥抗细胞凋亡作用，从而维持动脉粥样硬化斑块的稳定性。 PPAR δ 的特异性配体可能通过改善斑块稳定性和患者预后来帮助动脉粥样硬化的治疗干预。 （Circ Res. 2009；105：16-24。）
Homeostasis of the extracellular matrix and apoptosis of vascular smooth muscle cells (VSMCs) are key components in the regulation of the stability of atherosclerotic plaques. Here, we demonstrate that peroxisome proliferator-activated receptor (PPAR)delta regulates extracellular matrix synthesis and degradation through transforming growth factor-beta 1 and its effector, Smad3. Activation of PPAR delta strongly amplified the expression of types I and III collagen, fibronectin, elastin, and TIMP-3 (tissue inhibitor of metalloproteinases 3), but not of TIMP-1, matrix metalloproteinase-2 or -9. The effect of PPAR delta on the expression of type III collagen was dually regulated by the direct binding of PPAR delta and Smad3 to a direct repeat-1 site and a Smad-binding element, respectively, in the type III collagen gene promoter. The activation of PPAR delta attenuated apoptotic cell death in VSMCs induced by oxidized low-density lipoprotein, and similar antiapoptotic effects were observed on treatment of cells with exogenous type I and/or III collagen. Administration of a PPAR delta ligand GW501516 to mice also suppressed elastase-induced cell death of aortic VSMCs. These results suggest that PPAR delta-induced upregulation of extracellular matrix proteins exerts an antiapoptotic effect, thereby maintaining the stability of atherosclerotic plaques. Specific ligands of PPAR delta may aid in the therapeutic intervention of atherosclerosis by improving plaque stability and patient prognosis. (Circ Res. 2009; 105: 16-24.)