HDAC inhibition helps post-MI healing by modulating macrophage polarization.
HDAC inhibition helps post-MI healing by modulating macrophage polarization.
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DOI：
10.1016/j.yjmcc.2018.04.011
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发表时间：
2018-06
影响因子：
5
通讯作者：
Menick DR
中科院分区：
文献类型：
--
作者：
Kimbrough D;Wang SH;Wright LH;Mani SK;Kasiganesan H;LaRue AC;Cheng Q;Nadig SN;Atkinson C;Menick DR
急性心肌梗死（MI）后，细胞外基质（ECM）发生重塑，以防止梗死区扩张并维持心输出量。心肌梗死后过度和长期的炎症加重了心室重构。巨噬细胞是炎症反应的一个组成部分，有助于这种重塑。组蛋白去乙酰化酶（HDAC）抑制剂治疗可保护MI后心脏的LV功能和心肌重塑。本研究测试了HDAC活性的抑制是否通过调节巨噬细胞表型和炎症的早期消退来保护MI后LV功能。HDAC抑制不影响梗死后前3天内CD 45+白细胞、CD 45 +/CD 11b+炎性单核细胞或CD 45 +/CD 11b + CD 86+炎性巨噬细胞的募集。此外，HDAC抑制不会改变MI后第一天炎性细胞因子的高表达水平。然而，到第7天，在HDAC抑制的情况下，CD 45 +/Cd 11b+和CD 45 +/CD 11b +/CD 86+细胞的水平显著降低。值得注意的是，HDAC抑制导致早在第1天CD 45 +/CD 11b +/CD 206+交替活化的巨噬细胞的募集显著增加，其保持显著升高直至MI后5天。qRT-PCR显示，HDAC抑制剂处理使细胞因子和趋化因子环境向M2表型转变，在MI后1天和5天上调M2标志物。重要的是，HDAC抑制与LV射血分数和舒张末期容积的显著保留相关，并且与MI后14天边界区微血管密度的显著增加相关。HDAC活性的抑制导致MI后心脏中修复性CD 45 +/CD 11b +/CD 206+巨噬细胞的早期募集，并与心室功能和重塑的改善相关。这项工作确定了一个非常有前途的治疗机会，以管理巨噬细胞表型和提高MI后心脏炎症的解决。
Following an acute myocardial infarction (MI) the extracellular matrix (ECM) undergoes remodeling in order to prevent dilation of the infarct area and maintain cardiac output. Excessive and prolonged inflammation following an MI exacerbates adverse ventricular remodeling. Macrophages are an integral part of the inflammatory response that contribute to this remodeling. Treatment with histone deacetylase (HDAC) inhibitors preserves LV function and myocardial remodeling in the post-MI heart. This study tested whether inhibition of HDAC activity resulted in preserving post-MI LV function through the regulation of macrophage phenotype and early resolution of inflammation. HDAC inhibition does not affect the recruitment of CD45+ leukocytes, CD45+/CD11b+ inflammatory monocytes or CD45+/CD11b+CD86+ inflammatory macrophages for the first 3 days following infarct. Further, HDAC inhibition does not change the high expression level of the inflammatory cytokines in the first days following MI. However, by day 7, there was a significant reduction in the levels of CD45+/Cd11b+ and CD45+/CD11b+/CD86+ cells with HDAC inhibition. Remarkably, HDAC inhibition resulted in the dramatic increase in the recruitment of CD45+/CD11b+/CD206+ alternatively activated macrophages as early as 1 Day which remained significantly elevated until 5 days post-MI. qRT-PCR revealed that HDAC inhibitor treatment shifts the cytokine and chemokine environment towards an M2 phenotype with upregulation of M2 markers at 1 and 5 days post-MI. Importantly, HDAC inhibition correlates with significant preservation of both LV ejection fraction and end-diastolic volume and is associated with a significant increase in micro-vessel density in the border zone at 14 days post-MI. Inhibition of HDAC activity result in the early recruitment of reparative CD45+/CD11b+/CD206+ macrophages in the post-MI heart and correlates with improved ventricular function and remodeling. This work identifies a very promising therapeutic opportunity to manage macrophage phenotype and enhance resolution of inflammation in the post-MI heart.
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影响因子：
4.6
作者：
Gui T;Shimokado A;Sun Y;Akasaka T;Muragaki Y
通讯作者：
Muragaki Y
DOI：
10.1152/ajpheart.00390.2014
发表时间：
2015-06-01
影响因子：
4.8
作者：
Mani, Santhosh K.;Kern, Christine B.;Menick, Donald R.
通讯作者：
Menick, Donald R.
DOI：
10.1016/j.ddmec.2007.12.006
发表时间：
2007-01-01
期刊：
Drug discovery today. Disease mechanisms
影响因子：
--
作者：
French, Brent A;Kramer, Christopher M
通讯作者：
Kramer, Christopher M
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG
影响因子：
5.7
作者：
McKinsey, Timothy A.
通讯作者：
McKinsey, Timothy A.