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丁酸盐和曲古抑菌素 A 对血管平滑肌细胞的差异细胞和分子作用。

Differential cellular and molecular effects of butyrate and trichostatin a on vascular smooth muscle cells.

机构信息

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne St, Houston, TX 77004, USA.

出版信息

Pharmaceuticals (Basel). 2012 Sep 4;5(9):925-43. doi: 10.3390/ph5090925.

DOI:10.3390/ph5090925
PMID:24280698
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3816648/
Abstract

The histone deacetylase (HDAC) inhibitors, butyrate and trichostatin A (TSA), are epigenetic histone modifiers and proliferation inhibitors by downregulating cyclin D1, a positive cell cycle regulator, and upregulating p21Cip1 and INK family of proteins, negative cell cycle regulators. Our recent study indicated cyclin D1 upregulation in vascular smooth muscle cells (VSMC) that are proliferation-arrested by butyrate. Here we investigate whether cyclin D1 upregulation is a unique response of VSMC to butyrate or a general response to HDAC inhibitors (HDACi) by evaluating the effects of butyrate and TSA on VSMC. While butyrate and TSA inhibit VSMC proliferation via cytostatic and cytotoxic effects, respectively, they downregulate cdk4, cdk6, and cdk2, and upregulate cyclin D3, p21Cip1 and p15INK4B, and cause similar effects on key histone H3 posttranslational modifications. Conversely, cyclin D1 is upregulated by butyrate and inhibited by TSA. Assessment of glycogen synthase 3-dependent phosphorylation, subcellular localization and transcription of cyclin D1 indicates that differential effects of butyrate and TSA on cyclin D1 levels are linked to disparity in cyclin D1 gene expression. Disparity in butyrate- and TSA-induced cyclin D1 may influence transcriptional regulation of genes that are associated with changes in cellular morphology/cellular effects that these HDACi confer on VSMC, as a transcriptional modulator.

摘要

组蛋白去乙酰化酶 (HDAC) 抑制剂丁酸钠和曲古抑菌素 A (TSA) 通过下调细胞周期正向调控因子 cyclin D1 和上调细胞周期负向调控因子 p21Cip1 和 INK 家族蛋白来抑制增殖，是表观遗传组蛋白修饰剂。我们最近的研究表明，丁酸钠可使增殖静止的血管平滑肌细胞 (VSMC) 中 cyclin D1 上调。在此，我们通过评估丁酸钠和 TSA 对 VSMC 的影响，研究 cyclin D1 上调是否是 VSMC 对丁酸钠的特有反应，还是对 HDAC 抑制剂 (HDACi) 的一般反应。虽然丁酸钠和 TSA 分别通过细胞静止和细胞毒性作用抑制 VSMC 增殖，但它们下调 cdk4、cdk6 和 cdk2，上调 cyclin D3、p21Cip1 和 p15INK4B，并对关键组蛋白 H3 翻译后修饰产生类似的影响。相反，丁酸钠上调 cyclin D1，而 TSA 抑制 cyclin D1。对糖原合酶 3 依赖性磷酸化、cyclin D1 亚细胞定位和转录的评估表明，丁酸钠和 TSA 对 cyclin D1 水平的不同影响与 cyclin D1 基因表达的差异有关。丁酸钠和 TSA 诱导的 cyclin D1 的差异可能会影响这些 HDACi 赋予 VSMC 的细胞形态/细胞效应变化相关基因的转录调控，作为转录调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/c03a3716092a/pharmaceuticals-05-00925-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/5ffb20ffc91a/pharmaceuticals-05-00925-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/234fc93234d4/pharmaceuticals-05-00925-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/5ecd2082dee5/pharmaceuticals-05-00925-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/49491f2f9a12/pharmaceuticals-05-00925-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/c03a3716092a/pharmaceuticals-05-00925-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/5ffb20ffc91a/pharmaceuticals-05-00925-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/16c21c80b063/pharmaceuticals-05-00925-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/c180b5f990fb/pharmaceuticals-05-00925-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/a38ca20661f0/pharmaceuticals-05-00925-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/234fc93234d4/pharmaceuticals-05-00925-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/5ecd2082dee5/pharmaceuticals-05-00925-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/49491f2f9a12/pharmaceuticals-05-00925-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d28/3816648/c03a3716092a/pharmaceuticals-05-00925-g008.jpg

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