Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of α-MHC and cardiac tubulins:: implication for gain in cardiac muscle contractility
Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of α-MHC and cardiac tubulins:: implication for gain in cardiac muscle contractility
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DOI：
10.1152/ajpheart.00789.2004
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发表时间：
2005-03-01
影响因子：
4.8
通讯作者：
Gupta, MP
中科院分区：
文献类型：
--
作者：
Davis, FJ;Pillai, JB;Gupta, MP
组蛋白脱乙酰酶 (HDAC) 是一类酶，可催化去除核心组蛋白中的乙酰基，从而导致染色质结构和基因转录活性的变化。在心脏中，HDAC 是肥大信号传导的靶标，曲古抑菌素 A (TSA) 对 HDAC 的非特异性抑制可减弱培养的心肌细胞的肥大。在这项研究中，我们检查了 TSA 对心肌收缩力的两个主要决定因素的影响：α-肌球蛋白重链 (MHC) 表达和微管组成和组织。 TSA 上调培养的心肌细胞以及甲状腺功能减退大鼠体内模型中 α-MHC 的表达。旨在描述 TSA 诱导 α-MHC 机制的研究揭示了早期生长反应因子 1 对 α-MHC 启动子激活的必然作用。同时，TSA 下调 α 和 β 微管蛋白的表达，并阻止肥大激动剂 ANG II 对微管蛋白的诱导。 TSA 处理细胞后，ANG II 介导的与聚合微管相关的 α 和 β 微管蛋白比例增加也显着降低。免疫荧光显微镜结果表明，TSA 对对照细胞中心脏微管的组织没有明显影响，但它阻止 ANG II 诱导的密集平行线性微管阵列达到与对照细胞相似的轮廓。总之，这些结果表明，TSA 对 HDAC 的抑制可以以预测心脏收缩功能改善的方式调节心脏 α-MHC 和微管蛋白。这些研究提高了我们对 HDAC 在心脏肥大中的作用的理解，对开发治疗心脏异常的新治疗药物具有重要意义。
Histone deacetylases (HDACs) are a family of enzymes that catalyze the removal of acetyl groups from core histones, resulting in change of chromatin structure and gene transcription activity. In the heart, HDACs are targets of hypertrophic signaling, and their nonspecific inhibition by trichostatin A (TSA) attenuates hypertrophy of cultured cardiac myocytes. In this study, we examined the effect of TSA on two major determinants of cardiac contractility: alpha-myosin heavy chain (MHC) expression and microtubular composition and organization. TSA upregulated the expression of alpha-MHC in cultured cardiac myocytes, as well as in an in vivo model of hypothyroid rats. Studies designed to delineate mechanisms of alpha-MHC induction by TSA revealed an obligatory role of early growth response factor-1 on activation of the alpha-MHC promoter. Concurrently, TSA downregulated the expression of alpha- and beta-tubulins and prevented the induction of tubulins by a hypertrophy agonist, ANG II. The ANG II-mediated increased proportion of alpha- and beta- ubulins associated with polymerized microtubules was also markedly reduced after treatment of cells by TSA. Results obtained from immunofluorescent microscopy indicated that TSA had no noticeable effect on the organization of cardiac microtubules in control cells, whereas it prevented the ANG II-induced dense parallel linear arrays of microtubules to a profile similar to that of controls. Together, these results demonstrate that inhibition of HDACs by TSA regulates the cardiac alpha-MHC and tubulins in a manner predictive of improved cardiac contractile function. These studies improve our understanding of the role of HDACs on cardiac hypertrophy with implications in development of new therapeutic agents for treatment of cardiac abnormalities.