Naringin, an active flavonoid isolated from citrus fruit extracts, exhibits biological and pharmacological properties, such as antioxidant activity and antidiabetic effect. Mitogen-activated protein kinase (MAPK) signalling pathway has been shown to participate in hyperglycaemia-induced injury. The present study tested the hypothesis that naringin protects against high glucose (HG)-induced injuries by inhibiting MAPK pathway in H9c2 cardiac cells. To examine this, the cells were treated with 35 mM glucose (HG) for 24 hr to establish a HG-induced cardiomyocyte injury model. The cells were pre-treated with 80 lM naringin for 2 hr before exposure to HG. The findings of this study showed that exposure of H9c2 cells to HG for 24 hr markedly induced injuries, as evidenced by a decrease in cell viability, increases in apoptotic cells and reactive oxygen species (ROS) production, as well as dissipation of mitochondrial membrance potential (MMP). These injuries were significantly attenuated by the pre-treatment of cells with either naringin or SB203580 (a selective inhibitor of p38 MAPK) or U0126 (a selective inhibitor of extracellular signal regulated kinase 1/2, ERK1/2) or SP600125 (a selective inhibitor of c-jun N-termanal kinase, JNK) before exposure to HG, respectively. Furthermore, exposure of cells to HG increased the phosphorylation of p38 MAPK, ERK1/2 and JNK. The increased activation of MAPK pathway was ameliorated by pre-treatment with either naringin or N-acetyl-L-cysteine (NAC), a ROS scavenger, which also reduced HG-induced cytotoxicity and apoptosis, leading to increase in cell viability and decrease in apoptotic cells. In conclusion, our findings provide new evidence for the first time that naringin protects against HGinduced injuries by inhibiting the activation of MAPK (p38 MAPK, ERK1/2 and JNK) and oxidative stress in H9c2 cells.Hyperglycaemia, the most important feature of diabetes mellitus (DM), is believed to be a risk factor for the development of diabetic cardiovascular complications, such as diabetic cardiomyopathy (DCM) [1,2]. The mechanisms responsible for the deteriorative effects of hyperglycaemia on cardiomyocytes are complicated. Multiple factors, such as reactive oxygen species (ROS) production [3][4][5][6][7][8], decline of antioxidant defence systems [6-10], pro-inflammatory cytokine [11][12][13], activation of mitogen-activated protein kinase (MAPK) [14][15][16] and mitochondrial damage [17,18] have been reported to contribute to hyperglycaemia-induced injuries. Sustained hyperglycaemia has been identified as a principle mediator of ROS generation in diabetes [3,4,14,19], which leads to oxidative myocardial injury [14,20]. Furthermore, hyperglycaemia significantly increases phosphorylation of p38 MAPK and extracellular signal regulated kinase (ERK) 1/2 (members of MAPK) in left ventricle tissue of diabetic rats [14], the increased activation of MAPK is associated with the development of diabetic cardiomyopathy [14]. In streptozotocin (STZ)-induced diabetic rats, hyperglycaemia...
Recently, naringin (NAR; 4',5,7-trihydroxyflavanone-7-rhamnoglucoside) has been shown to have cardioprotective properties. However, the specific mechanisms underlying its cardioprotective effects remain unclear. In this study, we aimed to investigate the cardioprotective effects of NAR and the possible underlying molecular mechanisms in cardiomyocytes using high glucose (HG) to induce apoptosis in H9c2 cells. The effect of NAR on apoptosis was assessed by Annexin V and propidium iodide staining, and by determining the levels of active caspase-3, -8 and -9. The effect of NAR on mitochondrial dysfunction was assessed by the loss of mitochondrial membrane potential (MMP). Our results demonstrated that exposure to HG induced apoptosis and mitochondrial dysfunction in cardiomyocytes. Treatment with NAR significantly increased MMP and inhibited the activation of caspase-3, -8 and -9. NAR attenuated the HG-induced p38 and p53 phosphorylation, decreased mitochondrial Bax and Bak expression, prevented the release of cytochrome c and increased Bcl-2 expression. Pre-treatment with SB203580, a p38 inhibitor, also suppressed p53 phosphorylation and prevented the loss of MMP, as well as apoptosis in the HG-treated H9c2 cells. Taken together, these data demonstrate that NAR inhibits HG-induced apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway.
A growing body of evidence has demonstrated that microRNAs (miRs) have pivotal roles in the pathophysiological development mechanisms of diabetic cardiomyopathy (DCM). Previous studies have demonstrated that miR-186-5p was significantly decreased in DCM. In addition, it has recently been reported that an imbalance of miR-186 is associated with a variety of physiological and pathological processes. Therefore, the present study was designed to investigate the role of miR-186-5p in high glucose (HG)-induced cytotoxicity and apoptosis in AC16 cardiomyocytes. Reverse transcription-polymerase chain reaction was used to demonstrate the significant decrease in the level of miR-186-5p in HG-treated AC16 cells (P<0.05). Subsequently, it was clarified that pre-transfection with miR-186-5p mimic significantly ameliorated the effects of high glucose, which induced a significant decrease in the viability of AC16 cells (P<0.05) and increases in apoptosis, as evidenced by the appearance of apoptotic nucleus and the significant upregulation of apoptosis rate in AC16 cells (P<0.05). In addition, the significantly increased expression of caspase-3 induced by HG (P<0.01) was also reversed by miR-186-5p mimic (P<0.01). Conversely, transfection with miR-186-5p inhibitor significantly reduced the viability of AC16 cells (P<0.05) and promoted apoptosis (P<0.05) as well as the expression of caspase-3 in AC16 cells (P<0.01), indicating the beneficial role of miR-186-5p in the physiological process of HG-induced damage. In conclusion, these results suggest that the distribution of miR-186-5p contributes to HG-induced cytotoxicity and apoptosis in AC16 cardiomyocytes.
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