Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and-9 expression and preserves LV function postmyocardial infarction
Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and-9 expression and preserves LV function postmyocardial infarction
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DOI：
10.1152/ajpheart.00390.2014
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发表时间：
2015-06-01
影响因子：
4.8
通讯作者：
Menick, Donald R.
中科院分区：
文献类型：
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作者：
Mani, Santhosh K.;Kern, Christine B.;Menick, Donald R.
心肌梗死（MI）后左心室（LV）重构可导致LV扩张和LV泵功能障碍。MI后基质金属蛋白酶（MMPs）的诱导，特别是MMP-2和MMP-9，被认为对MI区域和最初未受影响的远端区域的LV和细胞外基质重塑造成有害影响。组蛋白脱乙酰酶（HDAC）是一类在病理条件下影响基因转录调控的酶。我们评估了I/IIb类和I类选择性HDAC抑制剂对MMP-2和MMP-9丰度的疗效，并确定治疗是否导致MI后不良LV和细胞外基质重塑的减弱和LV泵功能的改善。在MMP-9启动子报告小鼠中手术诱导MI，并在MI后随机用I/IIb类HDAC抑制剂治疗7天。MI后，LV扩张，LV泵功能障碍，MMP-9基因启动子的激活显着减弱与I/IIb类HDAC抑制剂tichostatin A或辛二酰异羟肟酸（伏罗尼他）治疗的小鼠相比，MI-只有小鼠。免疫组织化学染色和MMP-2和MMP-9的酶谱水平降低与无论是tichostatin A或suberanilohydroxamic酸治疗。I类HDAC活性在MI后显著增加。用选择性I类HDAC抑制剂PD-106治疗可降低MI后MMP-2和MMP-9的水平，并减弱MI后LV扩张和LV泵功能障碍，与I/IIb类HDAC抑制相似。总之，这些独特的发现表明，选择性抑制I类HDAC可能提供一种新的治疗手段，以减轻MI后的不良LV重塑。
Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.