Increased free Zn 2+ correlates induction of sarco(endo)plasmic reticulum stress via altered expression levels of Zn 2+ -transporters in heart failure

J Cell Mol Med. 2018 Mar;22(3):1944-1956. doi: 10.1111/jcmm.13480. Epub 2018 Jan 15.


Zn2+ -homoeostasis including free Zn2+ ([Zn2+ ]i ) is regulated through Zn2+ -transporters and their comprehensive understanding may be important due to their contributions to cardiac dysfunction. Herein, we aimed to examine a possible role of Zn2+ -transporters in the development of heart failure (HF) via induction of ER stress. We first showed localizations of ZIP8, ZIP14 and ZnT8 to both sarcolemma and S(E)R in ventricular cardiomyocytes (H9c2 cells) using confocal together with calculated Pearson's coefficients. The expressions of ZIP14 and ZnT8 were significantly increased with decreased ZIP8 level in HF. Moreover, [Zn2+ ]i was significantly high in doxorubicin-treated H9c2 cells compared to their controls. We found elevated levels of ER stress markers, GRP78 and CHOP/Gadd153, confirming the existence of ER stress. Furthermore, we measured markedly increased total PKC and PKCα expression and PKCα-phosphorylation in HF. A PKC inhibition induced significant decrease in expressions of these ER stress markers compared to controls. Interestingly, direct increase in [Zn2+ ]i using zinc-ionophore induced significant increase in these markers. On the other hand, when we induced ER stress directly with tunicamycin, we could not observe any effect on expression levels of these Zn2+ transporters. Additionally, increased [Zn2+ ]i could induce marked activation of PKCα. Moreover, we observed marked decrease in [Zn2+ ]i under PKC inhibition in H9c2 cells. Overall, our present data suggest possible role of Zn2+ transporters on an intersection pathway with increased [Zn2+ ]i and PKCα activation and induction of HF, most probably via development of ER stress. Therefore, our present data provide novel information how a well-controlled [Zn2+ ]i via Zn2+ transporters and PKCα can be important therapeutic approach in prevention/treatment of HF.

Keywords: endoplasmic reticulum stress; heart failure; intracellular zinc; left ventricle; zinc transporters.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Case-Control Studies
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism
  • Cations, Divalent
  • Cell Line
  • Doxorubicin / pharmacology
  • Endoplasmic Reticulum Stress / drug effects
  • Gene Expression Regulation
  • Heart Failure / genetics*
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Heart Failure / surgery
  • Heart Transplantation*
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Heart Ventricles / pathology
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Male
  • Middle Aged
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Myoblasts / pathology
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism
  • Rats
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Tunicamycin / pharmacology
  • Zinc / metabolism*
  • Zinc Transporter 8 / genetics*
  • Zinc Transporter 8 / metabolism


  • Cation Transport Proteins
  • Cations, Divalent
  • DDIT3 protein, human
  • Heat-Shock Proteins
  • SLC30A8 protein, human
  • SLC39A14 protein, human
  • SLC39A8 protein, human
  • Zinc Transporter 8
  • Tunicamycin
  • Transcription Factor CHOP
  • Doxorubicin
  • Protein Kinase C-alpha
  • Zinc
  • molecular chaperone GRP78