Key result
Slc39a8-null mice exhibit embryonic lethality and a cardiac phenotype similar to human left ventricular noncompaction due to impaired extracellular matrix degradation via the Zn/MTF1/Adamts axis.
Why the study?
Does genetic deletion of the zinc transporter Slc39a8 cause ventricular noncompaction in a mouse model?
Does genetic deletion of the zinc transporter Slc39a8 cause ventricular noncompaction in a mouse model?
The zinc transporter Slc39a8 is essential for cardiac ventricular compaction, and its deletion leads to a phenotype resembling left ventricular noncompaction via impaired ECM degradation.
Slc39a8 deletion produces LVNC-like phenotype in mice; leaves open relevance to human noncompaction and requires validation.
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.
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Lin et al. (2018) studied Left ventricular noncompaction (LVNC). Slc39a8 knockout vs. Wild-type was evaluated on Embryonic survival and cardiac ventricular compaction. Slc39a8-null mice exhibit embryonic lethality and a cardiac phenotype similar to human left ventricular noncompaction due to impaired extracellular matrix degradation via the Zn/MTF1/Adamts axis.
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