Induction of endoplasmic reticulum stress and changes in expression levels of Zn-transporters in hypertrophic rat heart.

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.