Isolated left ventricular noncompaction (LVNC) results from excessive trabeculation and impaired myocardial compaction during heart development. The extracellular matrix (ECM) that separates endocardium from myocardium plays a critical but poorly understood role in ventricular trabeculation and compaction. In an attempt to characterize solute carrier family 39 member 8–null (Slc39a8-null) mice, we discovered that homozygous null embryos do not survive embryogenesis and exhibit a cardiac phenotype similar to human LVNC. Slc39a8 encodes a divalent metal cation importer that has been implicated in ECM degradation through the zinc/metal regulatory transcription factor 1 (Zn/MTF1) axis, which promotes the expression of ECM-degrading enzymes, including Adamts metalloproteinases. Here, we have shown that Slc39a8 is expressed by endothelial cells in the developing mouse heart, where it serves to maintain cellular Zn levels. Furthermore, Slc39a8-null hearts exhibited marked ECM accumulation and reduction of several Adamts metalloproteinases. Consistent with the in vivo observations, knockdown of SLC39A8 in HUVECs decreased ADAMTS1 transcription by decreasing cellular Zn uptake and, as a result, MTF1 transcriptional activity. Our study thus identifies a gene underlying ventricular trabeculation and compaction development, and a pathway regulating ECM during myocardial morphogenesis.

中文翻译：

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锌转运蛋白 Slc39a8 对于心室致密至关重要


孤立性左心室致密化不全（LVNC）是由于心脏发育过程中小梁过度形成和心肌致密化受损所致。将心内膜与心肌分开的细胞外基质（ECM）在心室小梁形成和致密过程中发挥着关键但人们知之甚少的作用。在尝试表征溶质载体家族 39 成员 8-null ( Slc39a8 -null) 小鼠时，我们发现纯合子胚胎无法在胚胎发生中存活并表现出与人类 LVNC 相似的心脏表型。 Slc39a8编码二价金属阳离子输入蛋白，该输入蛋白通过锌/金属调节转录因子 1 (Zn/MTF1) 轴参与 ECM 降解，从而促进 ECM 降解酶（包括 Adamts 金属蛋白酶）的表达。在这里，我们发现Slc39a8由发育中的小鼠心脏的内皮细胞表达，其作用是维持细胞内的锌水平。此外， Slc39a8缺失的心脏表现出显着的ECM积累和几种Adamts金属蛋白酶的减少。与体内观察结果一致，HUVEC 中SLC39A8的敲低通过减少细胞 Zn 摄取来减少ADAMTS1转录，从而降低 MTF1 转录活性。因此，我们的研究确定了心室小梁形成和致密化发展的基因，以及心肌形态发生过程中调节 ECM 的途径。