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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Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

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 3

Slc39a8 deletion leads to decreased expression of Adamts metalloproteinases and impaired cardiac ECM degradation.

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Slc39a8 deletion leads to decreased expression of Adamts metalloprotein...
(A) qRT-PCR analysis showed decreased expression of Adamts metalloproteinases in Slc39a8–/– hearts at E12.5. n = 3 for each genotype. **P < 0.01. (B) Alcian blue staining showed that cardiac ECM was substantially increased in Slc39a8–/– hearts as compared with Slc39a8+/+ hearts at E12.5. Scale bars: 50 μm. (C) IF staining demonstrated that the immunoreactive signal of versican was greatly increased in Slc39a8–/– hearts, whereas DPEAAE was markedly reduced in Slc39a8–/– hearts as compared with Slc39a8+/+ hearts at E12.5. Scale bars: 200 μm. Western blot of DPEAAE on E12.5 Slc39a8+/+ and Slc39a8–/– hearts is shown on the right. n = 4 for each genotype. β-Actin was used as protein loading control. The densitometry analysis is shown at the right bottom panel. ***P < 0.001 by Student’s t test.