Open AccessIncreased free Zn 2+ correlates induction of sarco(endo)plasmic reticulum stress via altered expression levels of Zn 2+ ‐transporters in heart failure
Author(s) -
Olgar Yusuf,
Durak Aysegul,
Tuncay Erkan,
Bitirim Ceylan Verda,
Ozcinar Evren,
Inan Mustafa Bahadir,
TokcaerKeskin Zeynep,
Akcali Kamil Can,
Akar Ahmet Ruchan,
Turan Belma
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13480
Subject(s) - chemistry , homeostasis , transporter , medicine , protein kinase c , endocrinology , unfolded protein response , endoplasmic reticulum , zinc , signal transduction , biology , biochemistry , gene , organic chemistry
Zn 2+ ‐homoeostasis including free Zn 2+ ([Zn 2+ ] i ) is regulated through Zn 2+ ‐transporters and their comprehensive understanding may be important due to their contributions to cardiac dysfunction. Herein, we aimed to examine a possible role of Zn 2+ ‐transporters in the development of heart failure ( HF ) via induction of ER stress. We first showed localizations of ZIP 8, ZIP 14 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 ZIP 14 and ZnT8 were significantly increased with decreased ZIP 8 level in HF . Moreover, [Zn 2+ ] i was significantly high in doxorubicin‐treated H9c2 cells compared to their controls. We found elevated levels of ER stress markers, GRP 78 and CHOP /Gadd153, confirming the existence of ER stress. Furthermore, we measured markedly increased total PKC and PKC α expression and PKC α‐phosphorylation in HF . A PKC inhibition induced significant decrease in expressions of these ER stress markers compared to controls. Interestingly, direct increase in [Zn 2+ ] 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 Zn 2+ transporters. Additionally, increased [Zn 2+ ] i could induce marked activation of PKC α. Moreover, we observed marked decrease in [Zn 2+ ] i under PKC inhibition in H9c2 cells. Overall, our present data suggest possible role of Zn 2+ transporters on an intersection pathway with increased [Zn 2+ ] i and PKC α activation and induction of HF , most probably via development of ER stress. Therefore, our present data provide novel information how a well‐controlled [Zn 2+ ] i via Zn 2+ transporters and PKC α can be important therapeutic approach in prevention/treatment of HF .