Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

Abstract

Abstract. Hyperglycemia is a risk factor for the development of diabetic cardiovascular complications, which are associated with the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, we demonstrate the inhibitory effects of exogenous hydrogen sulfide (H 2 S) on the activation of the MAPK pathway. The aim of the present study was to determine whether exogenous H 2 S prevents high glucose (HG)-induced injury by inhibiting the activation of the p38 MAPK and extracellular signal-regulated kinase (ERK)1/2 (members of MAPK) pathways in cardiomyoblasts (H9c2 cells). The findings of the present study demonstrated that the treatment of H9c2 cells with HG (35 mM glucose) for 24 h not only significantly induced injury, including cytotoxicity, apoptosis, overproduction of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (MMP), but also upregulated the expression levels of phosphorylated (p)-p38 MAPK and p-ERK1/2. The increased expression levels of p-p38 MAPK and p-ERK1/2 were markedly reduced by pre-treatment of the H9c2 cells with 400 µM sodium hydrogen sulfide (NaHS; a donor of H 2 S) prior to exposure to 35 mM glucose. Importantly, pre-treatment of the cells with 400 µM NaHS or 3 µM SB203580 (a selective inhibitor of p38 MAPK) or 15 µM U0126 (a selective inhibitor of ERK1/2) attenuated the HG-induced cardiomyocyte injury, leading to an increase in cell viability and a decrease in the number of apoptotic cells, preventing ROS generation, as well as the loss of MMP. In addition, pre-treatment of the cells with 1,000 µM N-acetyl-L-cysteine (a ROS scavenger) prior to exposure to HG ameliorated the HG-induced cytotoxicity. Taken together, the data from the present study demonstrate for the first time, to our knowledge, that exogenous H 2 S exerts a protective effect against HG-induced injury by inhibiting the activation of the p38 MAPK and ERK1/2 pathways and preventing oxidative stress in H9c2 cells.

p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity

“…Hyperglycemia has been implicated in activation of p38mapk in various types of cells including endothelial cells, cardiomyoblasts, and dendritic cells [35][36][37]. This effect of glucose on p38mapk activation in endothelial cells is concentration-and time-dependent [37,38]. In our obesity mouse model, increase in fasting plasma glucose concentration, glucose intolerance, and insulin intolerance were demonstrated [12].…”

“…Activation of p38mapk involves multiple mechanisms which are not fully understood, yet [14]. Hyperglycemia has been implicated in activation of p38mapk in various types of cells including endothelial cells, cardiomyoblasts, and dendritic cells [35][36][37]. This effect of glucose on p38mapk activation in endothelial cells is concentration-and time-dependent [37,38].…”

Emerging role of hydrogen sulfide-microRNA crosstalk in cardiovascular diseases

“…Members of the MAPK family, p38-MAPK and ERK1/2, are upregulated in response to cellular stress, leading to cardiomyocyte apoptosis (50,156). p38-MAPK is induced in several disease conditions including hyperglycemia, I/R injury, and hypoxia (16,49,50,134,156).…”

“…DATS inhibits apoptosis by preventing caspase-3 activation, blunting phosphorylation of JNK and c-JUN, and inhibiting nuclear translocation of NF-B (80). H 2 S mitigates upregulation of ROS and prevents cell death associated with several disease states including hyperglycemia, hyper-homocysteinemia, smoke exposure, and I/R injury (49,54,144,145,156,165).…”

“…The pathophysiology includes cardiac dysfunction due to increased fibrosis and left ventricular hypertrophy (48). High glucose induces cardiovascular dysfunction by activating the PKC/diacylglycerol pathway, calcium dysregulation, inducing endoplasmic reticulum stress, and deregulating autophagy and apoptosis, which have been shown to be mitigated by H 2 S supplementation (9,80,89,156,164). Furthermore, plasma H 2 S levels are decreased in type 2 diabetic patients, high-fat diet-treated mice (type 2 diabetic patients), and streptozotocin-treated rats (9,64,66).…”