Department of Cardiovasology, The Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
Int J Mol Med. 2014 Mar;33(3):605-12. doi: 10.3892/ijmm.2014.1614. Epub 2014 Jan 7.
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.
瘦素是肥胖基因的产物，据报道，它有助于糖尿病患者心肌细胞肥大的发展，并激活心肌细胞中的 p38 丝裂原活化蛋白激酶 (MAPK) 途径。在这项研究中，我们证明了柚皮苷，一种柑橘类黄酮，通过调节 p38 MAPK 途径的激活，保护心肌细胞（H9c2 细胞）免受高糖（HG）诱导的凋亡。我们假设柚皮苷通过抑制 HG 诱导的 p38 MAPK 途径激活来防止 HG 诱导的损伤。我们的研究结果表明，H9c2 细胞暴露于 HG（35mmol/L）24 小时后，瘦素和瘦素受体的表达水平明显上调。然而，在 H9c2 细胞暴露于 HG 之前用 80μmol/L 柚皮苷处理 2 小时，可显著减弱瘦素和瘦素受体表达水平的增加。此外，在暴露于 HG 之前用 50ng/ml 瘦素拮抗剂（LA）处理细胞 24 小时，可显著改善 HG 诱导的磷酸化（p）-p38 MAPK 表达的增加。值得注意的是，细胞用 80μmol/L 柚皮苷或 50ng/ml LA 预处理可显著抑制 HG 诱导的损伤，导致细胞活力增加和总凋亡细胞数量减少，抑制活性氧（ROS）生成以及线粒体膜电位（MMP）耗散。总之，本研究的结果首次提供证据表明，瘦素诱导的 p38 MAPK 途径的激活参与了 HG 诱导的损伤，包括 H9c2 心脏细胞的细胞毒性、凋亡、ROS 生成和 MMP 耗散。我们的数据表明，柚皮苷通过抑制瘦素诱导的 p38 MAPK 途径激活来保护心脏细胞免受 HG 诱导的损伤。
