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An important energy supplier of cardiomyocytes is mitochondria, similar to other mammalian cells. Studies have demonstrated that any defect in the normal processes controlled by mitochondria can lead to abnormal ROS production, thereby high oxidative stress as well as lack of ATP. Taken into consideration, the relationship between mitochondrial dysfunction and overproduction of ROS as well as the relation between increased ROS and high-level release of intracellular labile Zn2+, those bring into consideration the importance of the events related with those stimuli in cardiomyocytes responsible from cellular Zn2+-homeostasis and responsible Zn2+-transporters associated with the Zn2+-homeostasis and Zn2+-signaling. Zn2+-signaling, controlled by cellular Zn2+-homeostatic mechanisms, is regulated with intracellular labile Zn2+ levels, which are controlled, especially, with the two Zn2+-transporter families; ZIPs and ZnTs. Our experimental studies in mammalian cardiomyocytes and human heart tissue showed that Zn2+-transporters localizes to mitochondria besides sarco(endo)plasmic reticulum and Golgi under physiological condition. The protein levels as well as functions of those transporters can re-distribute under pathological conditions, therefore, they can interplay among organelles in cardiomyocytes to adjust a proper intracellular labile Zn2+ level. In the present review, we aimed to summarize the already known Zn2+-transporters localize to mitochondria and function to stabilize not only the cellular Zn2+ level but also cellular oxidative stress status. In conclusion, one can propose that a detailed understanding of cellular Zn2+-homeostasis and Zn2+-signaling through mitochondria may emphasize the importance of new mitochondria-targeting agents for prevention and/or therapy of cardiovascular dysfunction in humans.

Background Metabolic syndrome (MetS) is a prevalent risk factor for cardiac dysfunction. Although SGLT2-inhibitors have important cardioprotective effects in hyperglycemia, their underlying mechanisms are complex and not completely understood. Therefore, we examined mechanisms of a SGLT2-inhibitor dapagliflozin (DAPA)-related cardioprotection in overweight insulin-resistant MetS-rats comparison with insulin (INSU), behind its glucose-lowering effect. Methods A 28-week high-carbohydrate diet-induced MetS-rats received DAPA (5 mg/kg), INSU (0.15 mg/kg) or vehicle for 2 weeks. To validate MetS-induction, we monitored all animals weekly by measuring body weight, blood glucose and HOMO-IR index, electrocardiograms, heart rate, systolic and diastolic pressures. Results DAPA-treatment of MetS-rats significantly augmented the increased blood pressure, prolonged Q–R interval, and low heart rate with depressed left ventricular function and relaxation of the aorta. Prolonged-action potentials were preserved with DAPA-treatment, more prominently than INSU-treatment, at most, through the augmentation in depressed voltage-gated K + -channel currents. DAPA, more prominently than INSU-treatment, preserved the depolarized mitochondrial membrane potential, and altered mitochondrial protein levels such as Mfn-1, Mfn-2, and Fis-1 as well as provided significant augmentation in cytosolic Ca 2+ -homeostasis. Furthermore, DAPA also induced significant augmentation in voltage-gated Na + -currents and intracellular pH, and the cellular levels of increased oxidative stress, protein-thiol oxidation and ADP/ATP ratio in cardiomyocytes from MetS rats. Moreover, DAPA-treatment normalized the increases in the mRNA level of SGLT2 in MetS-rat heart. Conclusions Overall, our data provided a new insight into DAPA-associated cardioprotection in MetS rats, including suppression of prolonged ventricular-repolarization through augmentation of mitochondrial function and oxidative stress followed by improvement of fusion–fission proteins, out of its glucose-lowering effect.

The prevalence of death from cardiovascular disease is significantly higher in elderly populations; the underlying factors that contribute to the age‐associated decline in cardiac performance are poorly understood. Herein, we identify the involvement of sodium/glucose co‐transporter gene (SGLT2) in disrupted cellular Ca2+‐homeostasis, and mitochondrial dysfunction in age‐associated cardiac dysfunction. In contrast to younger rats (6‐month of age), older rats (24‐month of age) exhibited severe cardiac ultrastructural defects, including deformed, fragmented mitochondria with high electron densities. Cardiomyocytes isolated from aged rats demonstrated increased reactive oxygen species (ROS), loss of mitochondrial membrane potential and altered mitochondrial dynamics, compared with younger controls. Moreover, mitochondrial defects were accompanied by mitochondrial and cytosolic Ca2+ ([Ca2+]i) overload, indicative of disrupted cellular Ca2+‐homeostasis. Interestingly, increased [Ca2+]i coincided with decreased phosphorylation of phospholamban (PLB) and contractility. Aged‐cardiomyocytes also displayed high Na+/Ca2+‐exchanger (NCX) activity and blood glucose levels compared with young‐controls. Interestingly, the protein level of SGLT2 was dramatically increased in the aged cardiomyocytes. Moreover, SGLT2 inhibition was sufficient to restore age‐associated defects in [Ca2+]i‐homeostasis, PLB phosphorylation, NCX activity and mitochondrial Ca2+‐loading. Hence, the present data suggest that deregulated SGLT2 during ageing disrupts mitochondrial function and cardiac contractility through a mechanism that impinges upon [Ca2+]i‐homeostasis. Our studies support the notion that interventions that modulate SGLT2‐activity can provide benefits in maintaining [Ca2+]i and cardiac function with advanced age.

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.

Zinc plays an important role in biological systems as bound and histochemically reactive labile Zn2+. Although Zn2+ concentration is in the nM range in cardiomyocytes at rest and increases dramatically under stimulation, very little is known about precise mechanisms controlling the intracellular distribution of Zn2+ and its variations during cardiac function. Recent studies are focused on molecular and cellular aspects of labile Zn2+ and its homeostasis in mammalian cells and growing evidence clarified the molecular mechanisms underlying Zn2+-diverse functions in the heart, leading to the discovery of novel physiological functions of labile Zn2+ in parallel to the discovery of subcellular localization of Zn2+-transporters in cardiomyocytes. Additionally, important experimental data suggest a central role of intracellular labile Zn2+ in excitation-contraction coupling in cardiomyocytes by shaping Ca2+ dynamics. Cellular labile Zn2+ is tightly regulated against its adverse effects through either Zn2+-transporters, Zn2+-binding molecules or Zn2+-sensors, and, therefore plays a critical role in cellular signaling pathways. The present review summarizes the current understanding of the physiological role of cellular labile Zn2+ distribution in cardiomyocytes and how a remodeling of cellular Zn2+-homeostasis can be important in proper cell function with Zn2+-transporters under hyperglycemia. We also emphasize the recent investigations on Zn2+-transporter functions from the standpoint of human heart health to diseases together with their clinical interest as target proteins in the heart under pathological condition, such as diabetes.

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Background: Diabetic patients have prolonged cardiac repolarization and higher risk of arrhythmia. Besides, diabetes activates the innate immune system, resulting in higher levels of plasmatic cytokines, which are described to prolong ventricular repolarization. Methods: We characterize a metabolic model of type 2 diabetes (T2D) with prolonged cardiac repolarization. Sprague-Dawley rats were fed on a high-fat diet (45% Kcal from fat) for 6 weeks, and a low dose of streptozotozin intraperitoneally injected at week 2. Body weight and fasting blood glucose were measured and electrocardiograms of conscious animals were recorded weekly. Plasmatic lipid profile, insulin, cytokines, and arrhythmia susceptibility were determined at the end of the experimental period. Outward K+ currents and action potentials were recorded in isolated ventricular myocytes by patch-clamp. Results: T2D animals showed insulin resistance, hyperglycemia, and elevated levels of plasma cholesterol, triglycerides, TNFα, and IL-1b. They also developed bradycardia and prolonged QTc-interval duration that resulted in increased susceptibility to severe ventricular tachycardia under cardiac challenge. Action potential duration (APD) was prolonged in control cardiomyocytes incubated 24 h with plasma isolated from diabetic rats. However, adding TNFα and IL-1b receptor blockers to the serum of diabetic animals prevented the increased APD. Conclusions: The elevation of the circulating levels of TNFα and IL-1b are responsible for impaired ventricular repolarization and higher susceptibility to cardiac arrhythmia in our metabolic model of T2D.

Mitochondrial dysfunction contributes to aging and diseases like neurodegeneration and cardiovascular disorders. Mitochondria transfer and transplantation (MTT) represent promising therapeutic strategies aimed at restoring cellular function by introducing functional mitochondria into damaged cells. However, challenges like transfer efficiency, stability, and cellular integration limit clinical application. Recent biotechnological advances—such as liposomes, extracellular vesicles, and surface modifications—enhance mitochondrial protection, targeting, and biocompatibility. This Perspective highlights recent progress in MTT, its therapeutic potential, and current limitations. We also discuss the need for scalable, clinically translatable approaches and appropriate regulatory frameworks to realize the full potential of mitochondria-based nanotherapies in modern medicine. Mitochondrial dysfunction is involved in several disease states, mitochondria transfer and transplantation have the potential to address this. Here, the authors review recent advancements and challenges with emphasis on the contribution and potential of biotechnology in mitochondria transfer and transplantation.

Azoramide is identified as a new compound with the dual properties for the improvement of ER-folding capacity in various cells as well as for the treatment of T2DM. Although the effect of azoramide in glucose-homeostasis in mammalians is not known very well, a limited number of experimental studies showed that it could improve the insulin sensitivity in genetically obese mice. Therefore, here, we aimed to investigate the direct effect of azoramide on insulin signaling in insulin-resistant (IR) cardiomyocytes using IR-modelled ventricular cardiomyocytes. This model was established in H9c2 cells using palmitic acid incubation (50-μM for 24-h). The development of IR in cells was verified by monitoring the cellular 2-DG6P uptake assays in these treated cells. The 2-DG6P uptake was 50% less in the IR-cells compared to the control cells, while azoramide treatment (20-μM for 48-h) could prevent fully that decrease. In addition, azoramide treatment markedly preserved the IR-induced less ATP production and high-ROS production in these IR-cells. Furthermore, this treatment prevented the functional changes in mitochondria characterized by depolarized mitochondrial membrane potential and mitochondrial fusion or fusion-related protein levels as well as cellular ATP level. Moreover, this treatment provided marked protection against IR-associated changes in the insulin signaling pathway in cells, including recovery in the phosphorylation of IRS1 and Akt as well as the protein level of GLUT4 and Akt. Our present results, for the first time, demonstrated that azoramide plays an important protective role in IR-cardiomyocytes, at most, protective action on mitochondria. Therefore, one can suggest that azoramide, as a novel regulator, can provide direct cardioprotection in the IR-heart, at most, via affecting mitochondria and can be a good candidate as a new drug for the treatment of IR-associated cardiovascular disorders in mammalians with systemic IR.

The matrix metalloproteinases (MMPs) contribute to matrix remodeling in diabetes via tissue degradation; however, their contributions can be different depending on the pathology. For instance, MMPs are elevated in acute stress hyperglycemia, whereas they can be degraded in chronic hyperglycemia. Since studies emphasize the possible cardioprotective effect of ticagrelor (Tica) beyond its antiplatelet action, we aimed to examine whether Tica treatment can reverse the depressed heart function of metabolic syndrome (MetS) rats via affecting the expression levels of MMPs. Tica treatment of high-carbohydrate-induced MetS rats could not affect significantly the depressed contractile activity of Langendorff-perfused heart preparations. On the other hand, the Tica treatment provided a significant recovery in the reduced relaxation activity of the aortic preparations from the same animals. Histological examination of the hearts demonstrated marked damages in Mets rats, such as increases in the number of foamy cells and accumulation of collagen fiber and increases in the elastic lamellar irregularity of tunica media, while Tica treatment provided a slight improvement in the structure of left ventricle tissue. We also could not obtain a significant reverse in the high cytosolic labile Zn2+ ([Zn2+]i) with the treatment of cardiomyocytes with Tica. Furthermore, Tica treatment of MetS rats could not significantly reverse the degraded protein levels of MMP-2 and MMP-9 in the heart, as well. Overall, we demonstrated that Tica treatment of MetS rats has no significant benefits on the depressed heart function, although provide a significant beneficial impact on vascular relaxation. This action of Tica may be through its lack of action on both MMP degradation and high [Zn2+]i, which can further precipitate in cleavage of extracellular matrix in the heart.