Zinc deficiency induces abnormal development of the myocardium by promoting SENP5 overexpression

PLoS One. 2020 Nov 19;15(11):e0242606. doi: 10.1371/journal.pone.0242606. eCollection 2020.

Abstract

Gestational zinc deficiency is a cause of congenital heart disease in the fetus, and sentrin/small ubiquitin-like modifier (SUMO)-specific proteases (SENPs) as deSUMOylation enzymes play a crucial role in the development of cardiac structures. However, current studies of the regulation and function of SENP in zinc-deficient status during heart development remain limited. In this study, SUMO1 modification was found to gradually decrease during heart development, and the level of SENP5 exhibited a similar trend to SUMO1 conjugation. In addition, zinc deficiency resulted in cardiac dysplasia, increased cell apoptosis, decreased cell viability, and differentiation inhibition of hiPSC-CMs. In order to investigate the function of SENP5 in zinc deficiency, hiPSC-CMs were transfected with SENP5 small interfering RNA. The negative effects of zinc lacking conditions were reversed with depletion of SENP5. It was confirmed that zinc deficiency induced abnormal differentiation of hiPSCs and increased apoptosis of hiPSC-CMs by promoting SENP5 overexpression, which led to cardiac dysplasia. Thus, it was concluded that SENP5 regulates the SUMO1 deconjugation during heart development and zinc deficiency may reduce conjugated SUMO by promoting SENP5 overexpression, which induces abnormal development of the myocardium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Line
  • Female
  • Gene Expression Regulation*
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Male
  • Mice
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Peptide Hydrolases / biosynthesis*
  • SUMO-1 Protein / metabolism
  • Zinc / deficiency*

Substances

  • SUMO-1 Protein
  • SUMO1 protein, human
  • Peptide Hydrolases
  • Senp5 protein, human
  • Zinc

Grants and funding

CW was supported by Binhai Health and Family Planning Commission Science and Technology Projects (http://wjw.tjbh.gov.cn/ grant no. 2014BWKZ006); XC was supported by Science and Technology Project of Tianjin Binhai New Area(http://kjj.tjbh.gov.cn/ grant no. 2018BWKY013); CZ was supported by Binhai Health and Family Planning Commission Science and Technology Projects (http://wjw.tjbh.gov.cn/ Grant No. 2019BWKQ030); XL was supported by Tianjin Natural Science Foundation of China (http://kxjs.tj.gov.cn/ Grant No. 19JCZDJC35200) and Tianjin Special Project of New Generation Artificial Intelligence Technology (http://kxjs.tj.gov.cn/ Grant No. 18ZXZNSY00260).