Inhibition of the leptin-induced activation of the p38 MAPK pathway contributes to the protective effects of naringin against high glucose-induced injury in H9c2 cardiac cells

Abstract

Leptin, a product of the obese gene, has been reported to contribute to the development of cardiomyocyte hypertrophy in patients with diabetes and to activate the p38 mitogen-activated protein kinase (MAPK) pathway in cardiomyocytes. In this study, we demonstrate that naringin, a citrus flavonone, protects cardiomyoblasts (H9c2 cells) against high glucose (HG)-induced apoptosis by modulating the activation of the p38 MAPK pathway. We investigated the hypothesis that naringin prevents HG-induced injury by inhibiting the leptin-induced activation of the p38 MAPK pathway in H9c2 cells. Our results demonstrated that the exposure of H9c2 cells to HG (35 mmol/l) for a 24 h markedly upregulated the expression levels of both leptin and leptin receptors. However, the increase in the expression levels of leptin and leptin receptors was greatly attenuated by treatment of the H9c2 cells with 80 µmol/l naringin 2 h prior to exposure to HG. In addition, treatment of the cells with 50 ng/ml leptin antagonist (LA) for 24 h prior to exposure to HG markedly ameliorated the increased expression of phosphorylated (p)-p38 MAPK induced by HG. Of note, pre-treatment of the cells with either 80 µmol/l naringin or 50 ng/ml LA markedly inhibited the HG-induced injury, leading to an increase in cell viability and a decrease in the total number of apoptotic cells, preventing reactive oxygen species (ROS) generation, as well as the dissipation of mitochondrial membrane potential (MMP). In conclusion, the findings of the present study provide the first evidence that the leptin-induced activation of the p38 MAPK pathway is involved in HG-induced injury, including cytotoxicity, apoptosis, ROS generation and the dissipation of MMP in H9c2 cardiac cells. Our data demonstrate that naringin protects cardiac cells against HG-induced injury by inhibiting the leptin-induced activation of the p38 MAPK pathway.

Exogenous H2S protects H9c2 cardiac cells against high glucose-induced injury and inflammation by inhibiting the activation of the NF-κB and IL-1β pathways

“…Consistent with our previous studies (5,6,10,18), exposure of the cells to 35 mM glucose for 24 h markedly increased the intracellular generation of ROS (Fig. 4B).…”

“…Multiple factors have been reported to contribute to hyperglycemia-induced cardiac damage, such as oxidative stress (3)(4)(5)(6), mitochondrial dysfunction (5)(6)(7)(8), apoptosis (5-9) and activation of several signaling molecules, including mitogen-activated protein kinase (MAPK) (3,5,10,11), leptin (6,12) and p53 (7,9). Another signaling molecule involved in hyperglycemia-induced cardiomyocyte damage may be nuclear factor-κB (NF-κB).…”

Angiotensin‐(1–7) protects cardiomyocytes against high glucose‐induced injuries through inhibiting reactive oxygen species‐activated leptin–p38 mitogen‐activated protein kinase/extracellular signal‐regulated protein kinase 1/2 pathways, but not the leptin–c‐Jun N‐terminal kinase pathway in vitro

“…As our previous studies reported, we showed that HG could have various degenerative effects, including cytotoxicity, apoptosis, oxidative stress and mitochondrial insult, as evidenced by the decreased cell viability, the increased apoptotic rate, the accumulation ROS generation and the loss of MMP. The ROS level is not only an oxidative stress indicator, but also one of the elements reflecting HG‐stimulated cardiomyocyte damage.…”

“…Then the activation of Janus tyrosine kinase (JAK) and signal transducers and activators of transcription are two main components in the leptin pathway. Additionally, we also previously reported that inhibition of the leptin‐induced activation of the p38 MAPK pathway contributed to the protection of naringin against HG‐induced injury in cardiac cells.…”

Effects of Polyphenols on Oxidative Stress-Mediated Injury in Cardiomyocytes

“…Pretreatment with naringin (5 or 80 µM) increased cells viability and reduced the number of apoptotic cells, and dissipation of mitochondrial membrane potential (MMP). Naringin protected H9c2 cardiomyocytes by inhibiting ROS production and activation of MAPKs [82,83,84]. Naringin also confered protection against A/R-induced injury in H9c2 cardiomyocytes.…”