Calcium Channel Blockers Act through Nuclear Factor Y to Control Transcription of Key Cardiac Genes
Calcium Channel Blockers Act through Nuclear Factor Y to Control Transcription of Key Cardiac Genes
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DOI：
10.1124/mol.112.078253
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发表时间：
2012-09-01
影响因子：
3.6
通讯作者：
Shalev, Anath
中科院分区：
文献类型：
--
作者：
Cha-Molstad, Hyunjoo;Xu, Guanlan;Shalev, Anath
第一代钙通道阻滞剂如维拉帕米是广泛使用的一类阻断L型钙通道的抗高血压药物。我们最近发现，他们也减少心脏表达的促凋亡硫氧还蛋白相互作用蛋白（TXNIP），这表明他们可能有不受重视的转录作用。通过使用TXNIP启动子缺失和突变的研究，我们发现，CCAAT元件介导维拉帕米诱导的转录抑制，并确定核因子Y（NFY）是负责任的转录因子评估过表达/敲低和荧光素酶和染色质免疫沉淀试验在心肌细胞和糖尿病小鼠体内接受口服维拉帕米。我们进一步发现NFY-DNA结合的增加与组蛋白H4去乙酰化和转录抑制有关，并通过抑制钙调磷酸酶信号传导介导。值得注意的是，这种新鉴定的维拉帕米-钙调磷酸酶-NFY信号级联所赋予的转录控制并不限于TXNIP，这表明它可能调节其他NFY靶点的表达。因此，维拉帕米诱导钙调神经磷酸酶-NFY信号通路，控制心脏基因转录和凋亡，从而可能影响心脏生物学在以前未认识到的方式。
First-generation calcium channel blockers such as verapamil are a widely used class of antihypertensive drugs that block L-type calcium channels. We recently discovered that they also reduce cardiac expression of proapoptotic thioredoxin-interacting protein (TXNIP), suggesting that they may have unappreciated transcriptional effects. By use of TXNIP promoter deletion and mutation studies, we found that a CCAAT element was mediating verapamil-induced transcriptional repression and identified nuclear factor Y (NFY) to be the responsible transcription factor as assessed by overexpression/knockdown and luciferase and chromatin immunoprecipitation assays in cardiomyocytes and in vivo in diabetic mice receiving oral verapamil. We further discovered that increased NFY-DNA binding was associated with histone H4 deacetylation and transcriptional repression and mediated by inhibition of calcineurin signaling. It is noteworthy that the transcriptional control conferred by this newly identified verapamil-calcineurin-NFY signaling cascade was not limited to TXNIP, suggesting that it may modulate the expression of other NFY targets. Thus, verapamil induces a calcineurin-NFY signaling pathway that controls cardiac gene transcription and apoptosis and thereby may affect cardiac biology in previously unrecognized ways.