Synthetic retinoid Am80 suppresses smooth muscle phenotypic modulation and in-stent neointima formation by inhibiting KLF5
Synthetic retinoid Am80 suppresses smooth muscle phenotypic modulation and in-stent neointima formation by inhibiting KLF5
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DOI：
10.1161/01.res.0000190613.22565.13
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发表时间：
2005-11-25
影响因子：
20.1
通讯作者：
Nagai, R
中科院分区：
文献类型：
--
作者：
Fujiu, K;Manabe, I;Nagai, R
平滑肌细胞（SMC）表型的调节在新生内膜形成中起着重要作用。我们最近证明，合成的视黄酸受体α-特异性激动剂Am 80抑制转录因子KLF 5的活性，这是血管损伤后新生内膜形成所必需的。在本研究中，我们的目的是进一步分析Am 80抑制KLF 5的机制，以及抑制KLF 5对SMC和血管病变形成的影响，并评估Am 80用于预防支架内新生内膜形成的潜力。我们发现Am 80抑制KLF 5的表达和转录功能。特别令人感兴趣的是，我们发现KLF 5与PDGF-A启动子上的未配体RAR/RXR异源二聚体形成转录活性复合物; Am 80破坏该复合物，从而抑制KLF 5依赖性转录激活。使用小干扰RNA敲除KLF 5抑制血清诱导的SMC分化标记基因表达下调，并且在小鼠中KLF 5的单倍不足减弱血管损伤后SMC的表型调节，表明KLF 5在SMC表型控制中起关键作用。Am 80增强了培养物中和血管壁内SMC分化标志物基因的表达，并且在兔支架放置模型中口服Am 80显著抑制了支架内新生内膜形成。总之，这些结果表明，KLF 5在血管损伤后SMC表型的控制中起重要作用，并表明使用全身递送和/或与药物洗脱支架一起递送的Am 80预防支架内新生内膜形成的可行性。
Modulation of smooth muscle cell (SMC) phenotype plays a central role in neointima formation. We recently demonstrated that Am80, a synthetic retinoic acid receptor alpha-specific agonist, inhibits the activity of the transcription factor KLF5, which is essential for neointima formation after vascular injury. In the present study, we aimed to further analyze the mechanism by which Am80 inhibits KLF5 and the effects of inhibiting KLF5 on SMCs and vascular lesion formation, as well as to evaluate potential of Am80 for use in the prevention of in-stent neointima formation. We found that Am80 inhibited both the expression and transcriptional function of KLF5. Of particular interest was our finding that KLF5 forms a transcriptionally active complex with unliganded RAR/RXR heterodimer on the PDGF-A promoter; Am80 disrupts this complex, thereby inhibiting KLF5-dependent transcriptional activation. Knocking down KLF5 using small interfering RNA suppressed serum-induced downregulation of SMC differentiation marker gene expression in cultured SMCs, and haploinsufficiency of KLF5 in mice attenuated phenotypic modulation of SMCs after vascular injury, indicating that KLF5 plays a key role in the control of SMC phenotype. Am80 augmented expression of the SMC differentiation marker genes in culture and within the vessel walls, and oral administration of Am80 significantly inhibited in- stent neointima formation in a rabbit stent-placement model. Taken together, these results demonstrate that KLF5 plays an important role in the control of SMC phenotype after vascular injury and suggest the feasibility of using Am80, delivered systemically and/or with a drug eluting stent, to prevent in-stent neointima formation.