Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Cardiology Development

Zinc transporter Slc39a8 is essential for cardiac ventricular compaction

  • Text
  • PDF
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

×

Figure 4

SLC39A8 knockdown in HUVECs results in decreased ADAMTS1 expression and MTF1 transcriptional activity.

Options: View larger image (or click on image) Download as PowerPoint

SLC39A8 knockdown in HUVECs results in decreased ADAMTS1 expression and...
(A) Western blot and densitometry analysis showed that SLC39A8 siRNA treatment resulted in efficient SLC39A8 knockdown in HUVECs. HUVECs were treated with SLC39A8 siRNAs or control scramble siRNAs for 24 hours. n = 4 for each condition. ***P < 0.001 by Student’s t test. (B) 65Zn uptake was significantly reduced in SLC39A8 siRNA–treated HUVECs as compared with that in control siRNA–treated cells. n = 4 for each group. ***P < 0.001 by Student’s t test. (C) qRT-PCR analysis of ADAMTS1 expression in HUVECs treated with SLC39A8 siRNA, TPEN, or ZnCl2. ADAMTS1 expression was significantly decreased in SLC39A8 siRNA–treated or TPEN-treated HUVECs, but increased in ZnCl2-treated HUVECs. n = 4 for each condition. **P < 0.01; ***P < 0.001 by Student’s t test. (D) A schematic representation of the MTF1 reporter assay is shown on the left. TRE, tandem response element. MTF1 transcriptional activities were significantly decreased in HUVECs treated with SLC39A8 siRNA or TPEN but significantly increased in HUVECs treated with ZnCl2 as compared with the corresponding controls (n = 8, n = 6, and n = 4 respectively). Firefly luciferase activities were normalized to that of Renilla. MTF1 reporter activities in each treatment condition were normalized to the average of the corresponding control groups. *P < 0.05, **P < 0.01 by Student’s t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts