Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

J Clin Invest. 2018 Feb 1;128(2):826-833. doi: 10.1172/JCI96993. Epub 2018 Jan 16.


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.

Keywords: Cardiology; Development; Extracellular matrix; Genetic diseases; Mouse models.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS1 Protein / metabolism
  • Alleles
  • Animals
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • DNA-Binding Proteins / metabolism
  • Endocardium / metabolism
  • Extracellular Matrix / metabolism
  • Female
  • Gene Deletion
  • Heart / embryology
  • Heart Ventricles / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myocardium / metabolism
  • Phenotype
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Transcription Factors / metabolism
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / pathology
  • Zinc / metabolism*


  • Cation Transport Proteins
  • DNA-Binding Proteins
  • RNA, Small Interfering
  • SLC39A8 protein, human
  • Slc39a8 protein, mouse
  • Transcription Factors
  • transcription factor MTF-1
  • ADAMTS1 Protein
  • ADAMTS1 protein, human
  • Zinc