Involvement of heat shock factor 1 in statin-induced transcriptional upregulation of endothelial thrombomodulin.
Involvement of heat shock factor 1 in statin-induced transcriptional upregulation of endothelial thrombomodulin.
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DOI：
10.1161/circresaha.108.174607
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发表时间：
2008-08-15
影响因子：
20.1
通讯作者：
Hauer-Jensen, Martin
中科院分区：
文献类型：
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作者：
Fu, Qiang;Wang, Junru;Boerma, Marjan;Berbee, Maaike;Qiu, Xiaohua;Fink, Louis M.;Hauer-Jensen, Martin
他汀类药物通过Kruppel样因子（KLF）家族成员的机制上调内皮血栓调节蛋白（TM）。虽然KLF在这一过程中有明确的牵连，但实验证据指出了其他机制。报告构建体的缺失/突变分析用于证明TM启动子中SP1/KLF元件的突变仅部分消除他汀类药物诱导的TM上调，而相关热休克元件（HSEs）和SP1/KLF元件的同时突变完全阻止他汀类药物诱导的TM上调，从而证明热休克因子（HSFs）的作用。我们进一步确定了他汀类药物增加TM启动子中HSF 1与HSEs结合的途径。具体而言，他汀类药物引起NO依赖性的HSF 1从热休克蛋白90（HSP 90），核转位的HSF 1，并结合到TM启动子中的HSEs的解离。他汀类药物还降低了HSF 1分子伴侣14-3-3β的核含量。除了减少TM的上调，抑制HSF 1减少他汀类药物诱导的组织纤溶酶原激活物（tPA）的上调，而血栓反应蛋白（TSP-1），纤溶酶原激活物抑制剂1（派-1），或结缔组织生长因子（CTGF）的下调不受影响。敲低14-3-3β或抑制HSF 1磷酸化增强了他汀类药物对TM和tPA的作用，但不影响TSP-1、派-1或CTGF。这些数据表明，HSF 1参与他汀类药物诱导的TM调节。他们还表明，类似的机制可能适用于他汀类药物上调的基因，而不是下调的基因。这些结果可能具有广泛的意义，并建议使用热休克蛋白调节剂选择性地调节多效性他汀类药物的影响。
Statins upregulate endothelial thrombomodulin (TM) by mechanisms that involve members of the Kruppel-like factor (KLF) family. While KLFs are unequivocally implicated in this process experimental evidence points to additional mechanisms. Deletion/mutation analysis of reporter constructs was used to demonstrate that mutation of the SP1/KLF element in the TM promoter only partially abolishes statin-induced TM upregulation whereas simultaneous mutation of relevant heat shock elements (HSEs) and SP1/KLF element completely prevents statin-induced TM upregulation, thus demonstrating a role for heat shock factors (HSFs). We further identified the pathway by which statins increase binding of HSF1 to HSEs in the TM promoter. Specifically, statins caused NO-dependent dissociation of HSF1 from heat shock protein 90 (HSP90), nuclear translocation of HSF1, and binding to HSEs in the TM promoter. Statins also decreased nuclear content of the HSF1 chaperone 14-3-3β. In addition to reducing TM upregulation, inhibition of HSF1 reduced statin-induced upregulation of tissue plasminogen activator (tPA), whereas, downregulation of thrombomospondin (TSP-1), plasminogen activator inhibitor 1 (PAI-1), or connective tissue growth factor (CTGF) was unaffected. Knockdown of 14-3-3β or inhibition of HSF1 phosphorylation enhanced the effect of statins on TM and tPA, but did not influence TSP-1, PAI-1, or CTGF. These data demonstrate that HSF1 is involved in statin-induced regulation of TM. They also suggest that analogous mechanisms may apply to genes that are upregulated by statins, but not to downregulated genes. These results may have broad implications and suggest the use of heat shock protein modulators to selectively regulate pleiotropic statin effects.