Increased free Zn²⁺ correlates induction of sarco(endo)plasmic reticulum stress via altered expression levels of Zn²⁺‐transporters in heart failure

Abstract

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.

Excess Dietary Zinc Intake in Neonatal Mice Causes Oxidative Stress and Alters Intestinal Host–Microbe Interactions

“…In contrast, CALU , ST3GAL4 , CRTC2 , SLC28A2 , and COMMD1 were downregulated. As has been previously reported in other systems, our data support a role for excess dietary Zn in the intestine in activating endoplasmic reticulum (ER) stress and signaling. Calumenin ( CALU ) is a calcium‐binding protein localized in the ER involved in functions including protein folding and sorting, and regulates the activity of SERCA2a and of the ryanodine receptor .…”

Understanding the common mechanisms of heart and skeletal muscle wasting in cancer cachexia

“…Of note, both skeletal and cardiac muscle catabolism occur in pancreatic cancer mouse models 48 and patients 11 . In the heart, ZIP14 is expressed at relatively high levels 49 , and is increased after doxorubicin treatment 50 , resulting in increased intracellular zinc levels and induction of sarcoplasmic reticulum stress 51 .…”

Upregulation of Zip14 correlates with induction of endoplasmic reticulum stress (ERS) in hypertrophied hearts of Dahl saltsensitive rats

“…Moreover, the zinc transporter Zip14 is closely related to inflammation and production of proinflammatory cytokines (Aydemir et al, 2012;Eizirik et al, 2012;Troche et al, 2016). Zip14 is also expressed in cardiac tissues and located in the plasma membrane, which promotes extracellular zinc into the cytosol and increases the concentration of zinc in the cytosol (Taylor et al, 2007;Olgar et al, 2018a). We observed higher expression levels of in cardiomyocytes were increased compared with the SHAM group.…”

“…Furthermore, the zinc trafficking and the activity of the Zip14 transporter are important for adapting to the ERSassociated chronic metabolic disorders, and the Zip14mediated transport of zinc is necessary for adapting ERS (Kim et al, 2017). Olgar et al (2018a) also reported that Zn 2+ correlates the induction of ERS through altering expressions of Zn 2+ -transporter, Zip14, in heart failure. Therefore, there might be a correlation between the Zip14 and the ERS.…”