Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway.
Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway.
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DOI：
10.1161/circresaha.122.320785
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发表时间：
2022-07-08
影响因子：
20.1
通讯作者：
Li, Deqiang
中科院分区：
文献类型：
--
作者：
Jang, Jihyun;Song, Guang;Pettit, Sarah M.;Li, Qinshan;Song, Xiaosu;Cai, Chen-leng;Kaushal, Sunjay;Li, Deqiang
心肌壁的建立需要来自非心肌组织的适当生长线索。在心脏发育过程中，心外膜和心外膜衍生细胞（EPDC）通过分泌包括成纤维细胞生长因子9（FGF 9）和胰岛素样生长因子2（IGF 2）的必需因子来指导心肌生长。然而，人们对心外膜分泌因子的调控机制知之甚少，特别是通过染色质修饰来调控心肌形成。本研究旨在探讨发育中的心外膜中组蛋白去乙酰化酶3（HDAC 3）是否以及如何调节心肌生长。采用各种细胞和小鼠模型结合生物化学和分子工具来研究HDAC 3在发育中的心外膜中的作用。我们在发育中的小鼠心外膜中删除了Hdac 3，突变的心脏表现出心室心肌壁发育不全，EPDC减少。用来自Hdac 3敲除（KO）小鼠心外膜细胞（MEC）的上清液培养的胚胎心肌细胞也显示出增殖降低。全基因组转录组学分析显示，Fgf 9和Igf 2在Hdac 3 KO MEC中显著下调。我们进一步发现Fgf 9和Igf 2的表达依赖于HDAC 3脱乙酰酶活性。补充FGF 9或IGF 2可以挽救Hdac 3 KO上清液治疗的心肌增殖缺陷。从机制上讲，我们鉴定了微小RNA（miR）-322和miR-503在Hdac 3 KO MEC和Hdac 3心外膜KO心脏中上调。在Hdac 3 KO MEC中，miR-322或miR-503的过表达抑制FGF 9和IGF 2的表达，而miR-322或miR-503的敲低恢复FGF 9和IGF 2的表达。我们的研究结果揭示了心外膜HDAC 3通过抑制miR-322/miR-503刺激FGF 9和IGF 2促进致密心肌生长的关键信号通路，为阐明先天性心脏病的病因学提供了新的见解，并提供了促进心肌再生的概念策略。
Establishment of the myocardial wall requires proper growth cues from nonmyocardial tissues. During heart development, the epicardium and epicardium-derived cell (EPDC)s instruct myocardial growth by secreting essential factors including fibroblast growth factor 9 (FGF9) and insulin-like growth factor 2 (IGF2). However, it is poorly understood how the epicardial secreted factors are regulated, in particular by chromatin modifications for myocardial formation. The current study is to investigate whether and how histone deacetylase 3 (HDAC3) in the developing epicardium regulates myocardial growth. Various cellular and mouse models in conjunction with biochemical and molecular tools were employed to study the role of HDAC3 in the developing epicardium. We deleted Hdac3 in the developing murine epicardium and mutant hearts showed ventricular myocardial wall hypoplasia with reduction of EPDCs. The cultured embryonic cardiomyocytes with supernatants from Hdac3 knockout (KO) mouse epicardial cells (MECs) also showed decreased proliferation. Genome-wide transcriptomic analysis revealed that Fgf9 and Igf2 were significantly downregulated in Hdac3 KO MECs. We further found that Fgf9 and Igf2 expression is dependent on HDAC3 deacetylase activity. The supplementation of FGF9 or IGF2 can rescue the myocardial proliferation defects treated by Hdac3 KO supernatant. Mechanistically, we identified that microRNA (miR)-322 and miR-503 were upregulated in Hdac3 KO MECs and Hdac3 epicardial KO hearts. Overexpression of miR-322 or miR-503 repressed FGF9 and IGF2 expression, while knockdown of miR-322 or miR-503 restored FGF9 and IGF2 expression in Hdac3 KO MECs. Our findings reveal a critical signaling pathway in which epicardial HDAC3 promotes compact myocardial growth by stimulating FGF9 and IGF2 through repressing miR-322/miR-503, providing novel insights in elucidating etiology of congenital heart defects, and conceptual strategies to promote myocardial regeneration.