The effects of the histone deacetylase inhibitor 4-phenylbutyrate on gap junction conductance and permeability.
The effects of the histone deacetylase inhibitor 4-phenylbutyrate on gap junction conductance and permeability.
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DOI：
10.3389/fphar.2013.00111
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发表时间：
2013
影响因子：
5.6
通讯作者：
Brink PR
中科院分区：
文献类型：
--
作者：
Kaufman J;Gordon C;Bergamaschi R;Wang HZ;Cohen IS;Valiunas V;Brink PR
纵向阻力是决定心脏动作电位传播的关键因素。动作电位传导速度与纵向电阻的平方根成正比。心肌纵向阻力的一个主要决定因素是缝隙连接通道，它由连接蛋白组成。在心室肌中，连接蛋白43(Cx43)是主要表达的连接蛋白。间隙结通道数量的减少将导致纵向电阻的增加，从而可能导致传导速度减慢，而通道数量的增加可能会导致传导速度的增加。我们试图确定已知的组蛋白脱乙酰酶(HDAC)抑制剂4-苯基丁酸酯(4-PB)对组蛋白脱乙酰酶(HDAC)的抑制是否导致连接电导和通透性的增加，这不是单通道单位电导改变的结果。这些实验是用稳定转染Cx43的HEK-293细胞和HeLa细胞进行的。Western印迹分析显示，随着4-PB浓度的增加，Cx43表达上调。采用全细胞膜片钳技术，分别测量结(GJ)电导和单位单通道电导。此外，荧光显微镜还检测了荧光黄(LY)的细胞间转移。本研究中的数据表明，4-PB能够增强Cx43缝隙连接的功能，LY染料转移和多通道和单通道数据以及Western印迹分析表明。作为推论，4-PB等药物通过增加细胞间的偶联作用，有可能减少缺血的影响。像4-PB这样的药物在预防心脏病方面是否有效还有待观察。
Longitudinal resistance is a key factor in determining cardiac action potential propagation. Action potential conduction velocity has been shown to be proportional to the square root of longitudinal resistance. A major determinant of longitudinal resistance in myocardium is the gap junction channel, comprised connexin proteins. Within the ventricular myocardium connexin43 (Cx43) is the dominantly expressed connexin. Reduced numbers of gap junction channels will result in an increase in longitudinal resistance creating the possibility of slowed conduction velocity while increased numbers of channels would potentially result in an increase in conduction velocity. We sought to determine if inhibition of histone deacetylase (HDAC) by 4-phenylbutyrate (4-PB), a known inhibitor of HDAC resulted in an increase in junctional conductance and permeability, which is not the result of changes in single channel unitary conductance. These experiments were performed using HEK-293 cells and HeLa cells stably transfected with Cx43. Following treatment with increasing concentrations of 4-PB up-regulation of Cx43 was observed via Western blot analysis. Junctional (gj) conductance and unitary single channel conductance were measured via whole-cell patch clamp. In addition intercellular transfer of lucifer yellow (LY) was determined by fluorescence microscopy. The data in this study indicate that 4-PB is able to enhance functional Cx43 gap junction coupling as indicated by LY dye transfer and multichannel and single channel data along with Western blot analysis. As a corollary, pharmacological agents such as 4-PB have the potential, by increasing intercellular coupling, to reduce the effect of ischemia. It remains to be seen whether drugs like 4-PB will be effective in preventing cardiac maladies.
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DOI：
10.1007/978-1-61779-021-8_19
发表时间：
2011-01-01
期刊：
REGENERATING THE HEART: STEM CELLS AND THE CARDIOVASCULAR SYSTEM
影响因子：
--
作者：
Donahue, J. Kevin;Laurita, Kenneth R.
通讯作者：
Laurita, Kenneth R.
DOI：
10.1016/j.biocel.2006.03.007
发表时间：
2006-01-01
影响因子：
4
作者：
Pointis, Georges
通讯作者：
Pointis, Georges
影响因子：
20.1
作者：
Valiunas, V;Beyer, EC;Brink, PR
通讯作者：
Brink, PR
影响因子：
20.1
作者：
Valiunas, V;Weingart, R;Brink, PR
通讯作者：
Brink, PR
影响因子：
3.4
作者：
Jia, Zhiheng;Bien, Harold;Entcheva, Emilia
通讯作者：
Entcheva, Emilia