Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development.
Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development.
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DOI：
10.1161/circresaha.113.301324
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发表时间：
2013-06-21
影响因子：
20.1
通讯作者：
Chun HJ
中科院分区：
文献类型：
--
作者：
Kang Y;Kim J;Anderson JP;Wu J;Gleim SR;Kundu RK;McLean DL;Kim JD;Park H;Jin SW;Hwa J;Quertermous T;Chun HJ
肽配体爱帕琳及其受体APJ构成了对心血管系统具有多种影响的信号传导途径，包括在模式生物如爪蟾和斑马鱼中的心血管发育。本研究旨在表征Apj−/−小鼠的胚胎致死表型，并确定相关的下游信号传导靶点。我们报告了Apj−/−小鼠胚胎致死性的第一个特征。超过一半的预期Apj−/−胚胎由于心血管发育缺陷而在子宫内死亡。那些死于早期胚胎死亡的人的卵黄囊和胚胎的血管系统明显变形，以及右心室形成异常和房室垫形成缺陷的环形心脏。存活到后期的Apj−/−胚胎表现出由于血管平滑肌细胞缺乏而导致的血管不完全成熟，以及心肌小梁形成和心室壁发育受损。该分子机制涉及apelin-APJ下游涉及Gα13的新型非经典信号传导途径，其诱导组蛋白脱乙酰酶（HDAC）4和HDAC 5磷酸化和细胞质易位，导致MEF 2（肌细胞增强因子2）活化。Apj−/−小鼠具有更高的内分泌Hdac 4和Hdac 5核定位，并降低MEF 2转录靶Klf 2的表达。我们在内皮细胞中鉴定了apelin-APJ、Gα13和MEF 2之间的一些共有转录靶点，这些靶点在Apj−/−胚胎和内皮细胞中显著降低。我们的研究结果表明，apelin-APJ信号作为一种有效的调节内皮细胞MEF 2功能在心血管系统的发展新的作用。
The peptide ligand apelin and its receptor APJ constitute a signaling pathway with numerous effects on the cardiovascular system, including cardiovascular development in model organisms such as xenopus and zebrafish. This study aimed to characterize the embryonic lethal phenotype of the Apj−/− mice and define the involved downstream signaling targets. We report the first characterization of the embryonic lethality of the Apj−/− mice. Greater than half of the expected Apj−/− embryos died in utero due to cardiovascular developmental defects. Those succumbing to early embryonic death had markedly deformed vasculature of the yolk sac and the embryo, as well as poorly looped hearts with aberrantly formed right ventricles and defective atrioventricular cushion formation. Apj−/− embryos surviving to later stages demonstrated incomplete vascular maturation due to a deficiency of vascular smooth muscle cells, and impaired myocardial trabeculation and ventricular wall development. The molecular mechanism implicates a novel, non-canonical signaling pathway downstream of apelin-APJ involving Gα13, which induces histone deacetylase (HDAC) 4 and HDAC5 phosphorylation and cytoplasmic translocation, resulting in activation of MEF2 (myocyte enhancer factor 2). Apj−/− mice have greater endocardial Hdac4 and Hdac5 nuclear localization, and reduced expression of the MEF2 transcriptional target Klf2. We identify a number of commonly shared transcriptional targets among apelin-APJ, Gα13, and MEF2 in endothelial cells, which are significantly decreased in the Apj−/− embryos and endothelial cells. Our results demonstrate a novel role for apelin-APJ signaling as a potent regulator of endothelial MEF2 function in the developing cardiovascular system.