Abstract
Aging is an important risk factor for cardiac dysfunction. Heart during aging exhibits a depressed mechanical activity, at least, through mitochondria-originated increases in ROS. Previously, we also have shown a close relationship between increased ROS and cellular intracellular free Zn2+ ([Zn2+]i) in cardiomyocytes under pathological conditions as well as the contribution of some re-expressed levels of Zn2+-transporters for redistribution of [Zn2+]i among suborganelles. Therefore, we first examined the cellular (total) [Zn2+] and then determined the protein expression levels of Zn2+-transporters in freshly isolated ventricular cardiomyocytes from 24-month rat heart compared to those of 6-month rats. The [Zn2+]i in the aged-cardiomyocytes was increased, at most, due to increased ZIP7 and ZnT8 with decreased levels of ZIP8 and ZnT7. To examine redistribution of the cellular [Zn2+]i among suborganelles, such as Sarco/endoplasmic reticulum, S(E)R, and mitochondria ([Zn2+]SER and [Zn2+]Mit), a cell model (with galactose) to mimic the aged-cell in rat ventricular cell line H9c2 was used and demonstrated that there were significant increases in [Zn2+]Mit with decreases in [Zn2+]SER. In addition, the re-distribution of these Zn2+-transporters were markedly changed in mitochondria (increases in ZnT7 and ZnT8 with no changes in ZIP7 and ZIP8) and S(E)R (increase in ZIP7 and decrease in ZnT7 with no changes in both ZIP8 and ZnT8) both of them isolated from freshly isolated ventricular cardiomyocytes from aged-rats. Furthermore, we demonstrated that cellular levels of ROS, both total and mitochondrial lysine acetylation (K-Acetylation), and protein-thiol oxidation were significantly high in aged-cardiomyocytes from 24-month old rats. Using a mitochondrial-targeting antioxidant, MitoTEMPO (1 µM, 5-h incubation), we provided an important data associated with the role of mitochondrial-ROS production in the [Zn2+]i-dyshomeostasis of the ventricular cardiomyocytes from 24-month old rats. Overall, our present data, for the first time, demonstrated that a direct mitochondria-targeting antioxidant treatment can be a new therapeutic strategy during aging in the heart through a well-controlled [Zn2+] distribution among cytosol and suborganelles with altered expression levels of the Zn2+-transporters.
Highlights
Aging in humans is programmed genetically and modified by environmental influences as well as having a combination of morphological and functional changes in organs, tissues, and cells [1]
We have recently shown that the high [Zn2+]i could induce marked activation in ATP-sensitive K+-channel currents, depending on the cellular ATP levels [27], while a depletion in ATP production in insulin-resistant rat ventricular cardiomyocytes could induce significant prolongation in action potentials [6,28]
There was a significant presence of insulin resistance in the old group with the measurement of oral glucose tolerance test (OGTT) and homeostasis model assesment of of insulin resistance (HOMA-IR) index, as described previously [6]
Summary
Aging in humans is programmed genetically and modified by environmental influences as well as having a combination of morphological and functional changes in organs, tissues, and cells [1]. The rate of aged human percentage among populations is accelerating all over the world. The effect of aging can vary widely from one to another individual [2]. High resistance to blood pumping and increased workload against the increased resistance are the general findings in aged individuals [3]. Recent and even early both clinical and experimental studies mentioned that QT-intervals in electrocardiogram were prolonged with age in an overtly healthy older population [4,5,6,7]. The production of an increasing amount of lipid peroxidation and its accumulation into the heart during aging can increase the susceptibility to the development of cardiovascular diseases besides others, at most, due to the production of reactive oxygen species (ROS)
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