Ankara University Faculty of Medicine, Ankara, Turkey.
Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya, Turkey.
Mol Cell Biochem. 2018 Mar;440(1-2):209-219. doi: 10.1007/s11010-017-3168-9. Epub 2017 Aug 28.
Clinical and experimental studies have shown an association between intracellular free Zn ([Zn])-dyshomeostasis and cardiac dysfunction besides [Ca]-dyshomeostasis. Since [Zn]-homeostasis is regulated through Zn-transporters depending on their subcellular distributions, one can hypothesize that any imbalance in Zn-homeostasis via alteration in Zn-transporters may be associated with the induction of ER stress and apoptosis in hypertrophic heart. We used a transverse aortic constriction (TAC) model to induce hypertrophy in young male rat heart. We confirmed the development of hypertrophy with a high ratio of heart to body weight and cardiomyocyte capacitance. The expression levels of ER stress markers GRP78, CHOP/Gadd153, and calnexin are significantly high in TAC-group in comparison to those of controls (SHAM-group). Additionally, we detected high expression levels of apoptotic status marker proteins such as the serine kinase GSK-3β, Bax-to-Bcl-2 ratio, and PUMA in TAC-group in comparison to SHAM-group. The ratios of phospho-Akt to Akt and phospho-NFκB to the NFκB are significantly higher in TAC-group than in SHAM-group. Furthermore, we observed markedly increased phospho-PKCα and PKCα levels in TAC-group. We, also for the first time, determined significantly increased ZIP7, ZIP14, and ZnT8 expressions along with decreased ZIP8 and ZnT7 levels in the heart tissue from TAC-group in comparison to SHAM-group. Furthermore, a roughly calculated total expression level of ZIPs responsible for Zn-influx into the cytosol (increased about twofold) can be also responsible for the markedly increased [Zn] detected in hypertrophic cardiomyocytes. Taking into consideration the role of increased [Zn] via decreased ER-[Zn] in the induction of ER stress in cardiomyocytes, our present data suggest that differential changes in the expression levels of Zn-transporters can underlie mechanical dysfunction, in part due to the induction of ER stress and apoptosis in hypertrophic heart via increased [Zn]- besides [Ca]-dyshomeostasis.
临床和实验研究表明，细胞内游离锌 ([Zn]) 稳态失调与心脏功能障碍有关，除了钙稳态失调。由于锌稳态是通过根据亚细胞分布的锌转运蛋白来调节的，因此可以假设通过改变锌转运蛋白引起的锌稳态失衡可能与肥厚心脏中内质网应激和细胞凋亡的诱导有关。我们使用横主动脉缩窄 (TAC) 模型在年轻雄性大鼠心脏中诱导肥厚。我们通过心脏与体重的高比值和心肌细胞电容证实了肥厚的发展。与对照组 (SHAM 组) 相比，TAC 组内质网应激标志物 GRP78、CHOP/Gadd153 和钙连蛋白的表达水平显著升高。此外，我们还检测到 TAC 组中凋亡状态标志物蛋白如丝氨酸激酶 GSK-3β、Bax-to-Bcl-2 比值和 PUMA 的高表达水平与 SHAM 组相比。TAC 组中磷酸化 Akt 与 Akt 的比值和磷酸化 NFκB 与 NFκB 的比值明显高于 SHAM 组。此外，我们还观察到 TAC 组中磷酸化 PKCα 和 PKCα 水平明显增加。我们还首次确定 TAC 组心脏组织中 ZIP7、ZIP14 和 ZnT8 的表达明显增加，而 ZIP8 和 ZnT7 的水平降低。此外，还可以粗略计算负责 Zn 流入细胞质的 ZIPs 的总表达水平（增加约两倍），这也可能是在肥厚心肌细胞中检测到的 [Zn] 明显增加的原因。考虑到通过内质网中减少的 [Zn] 增加 [Zn] 在诱导心肌细胞内质网应激中的作用，我们目前的数据表明，锌转运蛋白表达水平的差异变化可能是机械功能障碍的部分原因，部分原因是通过增加 [Zn] 除了 [Ca] 稳态失调外，在肥厚心脏中诱导内质网应激和细胞凋亡。
