Tiron ameliorates high glucose‐induced cardiac myocyte apoptosis by PKCδ‐dependent inhibition of osteopontin

Abstract

Tiron functions as an effective antioxidant alleviating the intracellular reactive oxygen species (ROS) or the acute toxic metal overload. Previous studies have shown that cardiac myocyte apoptosis can be effectively inhibited by tiron administration in streptozotocin (STZ)-induced diabetic rats, primary neonatal rat cardiomyocytes (NRVMs), and H9c2 embryonic rat cardiomyocytes. However, the underlying signalling mechanism is ill-defined. In the present study, we found that tiron supplementation significantly inhibited apoptosis of high glucose (HG)-treated NRVMs and the left ventricular cardiomyocytes from STZ-diabetic rat, accompanied with a reduction of osteopontin (OPN) levels as well as an inhibition of PKCδ phosphorylation. OPN knockdown protected NRVMs against HG-induced cell apoptosis. In addition, genetic inhibition of PKCδ mitigated HG-stimulated enhancement of intracellular OPN levels in NRVMs. These findings indicate that ROS-mediated activation of PKCδ upregulated OPN expression, leading to cardiac myocyte apoptosis. Interfering with ROS/PKCδ pathway by antioxidants such as tiron provides an optional therapeutic strategy for treatment and prevention of apoptosis-related cardiovascular diseases including diabetic cardiomyopathy.

Comparative Histological Study on the Effect of Stem Cells, and Gene Modified Stem Cells in Experimentally-Induced Diabetes Type 1 Cardiomyopathy

“…In support, these changes were recently attributed to upregulation of reactive oxygen species (ROS) [30] . Furthermore, another group [31] added and confirmed by proving that using a potent antioxidant as tiron could interfere with ROS pathway and hence prevents apoptosis-related cardiovascular diseases including diabetic cardiomyopathy.…”

Heat shock protein 60 (HSP60) modulates adiponectin signaling by stabilizing adiponectin receptor

“…Hyperglycemia is a hallmark feature of both type 1 and type 2 diabetes. Previous study has evidenced that high levels of glucose induce oxidative stress and cell apoptosis in cardiomyocytes [30,42], which can be protected by adiponectin administration [43]. Using this model, we wanted to further confirm the role of HSP60 in mediating adiponectin signaling.…”

“…High glucose treatment was performed as our described previously [29,30]. The control group received the treatment of 5.5 mM glucose and the identical concentration of mannitol which act as osmotic control to remove a hyperosmolar effect.…”

“…Immunofluorescence staining was performed as our described previously [6,30]. Images were acquired on an Olympus IX83 laser scanning confocal microscope and analyzed by Olympus FV1200 software.…”

“…The real-time formation of ROS in cells was detected by dihydroergotamine (DHE) staining as described previously [30]. Briefly, the cells were plated on the coverslips within a 24-well plate at a density of 2 × 10 4 cells/well, starved serum for 6 h, and then treated with or without high glucose and/or other compound for the desired time.…”