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

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 PKC phosphorylation. OPN knockdown protected NRVMs against HG-induced cell apoptosis. In addition, genetic inhibition of PKC mitigated HG-stimulated enhancement of intracellular OPN levels in NRVMs. These findings indicate that ROS-mediated activation of PKC upregulated OPN expression, leading to cardiac myocyte apoptosis. Interfering with ROS/PKC pathway by antioxidants such as tiron provides an optional therapeutic strategy for treatment and prevention of apoptosis-related cardiovascular diseases including diabetic cardiomyopathy.