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Zinc transporter Slc39a8 is essential for cardiac ventricular compaction
Wen Lin, … , Jonathan A. Epstein, Daniel J. Rader
Wen Lin, … , Jonathan A. Epstein, Daniel J. Rader
Published January 16, 2018
Citation Information: J Clin Invest. 2018;128(2):826-833. https://doi.org/10.1172/JCI96993.
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Research Article Cardiology Development

Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

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Abstract

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.

Authors

Wen Lin, Deqiang Li, Lan Cheng, Li Li, Feiyan Liu, Nicholas J. Hand, Jonathan A. Epstein, Daniel J. Rader

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Figure 1

Slc39a8 is expressed in the developing hearts and regulates Zn levels.

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Slc39a8 is expressed in the developing hearts and regulates Zn levels.
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(A) qRT-PCR analysis of Slc39a8 in the whole heart at different developmental stages. Gapdh was used as cDNA loading control. n = 3 for each time point. (B) RNA in situ hybridization showed that Slc39a8 is expressed in the trabecular region of E12.5 hearts. Scale bars: 250 μm. (C) qRT-PCR analysis showed that Slc39a8 was efficiently deleted in E12.5 Slc39a8–/– hearts. n = 3 for each genotype. (D) ICP-MS analysis showed that Zn was reduced in E14.5 Slc39a8–/– hearts as compared with Slc39a8+/+ hearts. Results were normalized to protein content. *P = 0.06 by Student’s t test.

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