Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition.
Histone Deacetylase Inhibitor Phenylbutyrate Exaggerates Heart Failure in Pressure Overloaded Mice independently of HDAC inhibition.
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组蛋白脱乙酰酶抑制剂苯丁酸会加剧压力超负荷小鼠的心力衰竭，与 HDAC 抑制无关
DOI：
10.1038/srep34036
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发表时间：
2016-09-26
影响因子：
4.6
通讯作者：
Kitakaze M
中科院分区：
文献类型：
--
作者：
Ma J;Luo T;Zeng Z;Fu H;Asano Y;Liao Y;Minamino T;Kitakaze M
4-苯丁酸钠（PBA）已被报道抑制内质网应激和组蛋白去乙酰化（HDAC），这两者都是治疗心肌肥厚和心力衰竭的新靶点。然而，目前还不清楚PBA是否能改善心脏功能。在这里，我们测试了PBA和其他一些HDAC抑制剂对压力超负荷引起的心功能不全的影响。对雄性C57 BL/6小鼠进行横向主动脉缩窄（TAC）。PBA治疗（100 mg/kg，6周）意外地导致更高的死亡率，加重心脏重塑和功能障碍。在用丁酸钠（BS）（PBA类似物）处理的TAC小鼠中注意到类似的结果。相反，其他HDAC抑制剂，丙戊酸（瓦尔）和阿司他丁A（TSA），提高了生存率。所有四种HDAC抑制剂均诱导组蛋白H3乙酰化并抑制HDAC总活性。个体HDAC活性测定显示，PBA和BS主要抑制I类成员（HDAC 2和8），而不是II类成员（HDAC 4和7），而瓦尔和TSA抑制所有这些。这些发现表明PBA和BS加速心脏肥大和功能障碍，而瓦尔和TSA具有相反的作用。
4-Sodium phenylbutyrate (PBA) has been reported to inhibit endoplasmic reticulum stress and histone deacetylation (HDAC), both of which are novel therapeutic targets for cardiac hypertrophy and heart failure. However, it is unclear whether PBA can improve heart function. Here, we tested the effects of PBA and some other HDAC inhibitors on cardiac dysfunction induced by pressure overload. Transverse aortic constriction (TAC) was performed on male C57BL/6 mice. PBA treatment (100 mg/kg, 6 weeks) unexpectedly led to a higher mortality, exacerbated cardiac remodelling and dysfunction. Similar results were noted in TAC mice treated with butyrate sodium (BS), a PBA analogue. In contrast, other HDAC inhibitors, valproic acid (VAL) and trichostatin A (TSA), improved the survival. All four HDAC inhibitors induced histone H3 acetylation and inhibited HDAC total activity. An individual HDAC activity assay showed that rather than class IIamembers (HDAC4 and 7), PBA and BS predominantly inhibited class I members (HDAC2 and 8), whereas VAL and TSA inhibited all of them. These findings indicate that PBA and BS accelerate cardiac hypertrophy and dysfunction, whereas VAL and TSA have opposing effects.
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影响因子：
4.2
作者：
Fass, Daniel M.;Shah, Rishita;Ghosh, Balaram;Hennig, Krista;Norton, Stephanie;Zhao, Wen-Ning;Reis, Surya A.;Klein, Peter S.;Mazitschek, Ralph;Maglathlin, Rebecca L.;Lewis, Timothy A.;Haggarty, Stephen J.
通讯作者：
Haggarty, Stephen J.
影响因子：
5.3
作者：
Ma, KW;Chan, JKL;Wu, ZG
通讯作者：
Wu, ZG
影响因子：
5.3
作者：
Chang, SR;McKinsey, TA;Olson, EN
通讯作者：
Olson, EN
影响因子：
15.9
作者：
Maillet, Marjorie;Lynch, Jeffrey M.;Molkentin, Jeffery D.
通讯作者：
Molkentin, Jeffery D.
影响因子：
3.6
作者：
Ayala, Pedro;Montenegro, Jose;Diaz-Araya, Guillermo
通讯作者：
Diaz-Araya, Guillermo