You Qiong, Wu Zijun, Wu Bin, Liu Chang, Huang Ruina, Yang Li, Guo Runmin, Wu Keng, Chen Jingfu
Department of CardiovasologyThe Affiliated Hospital, Guangdong Medical College, Guangdong, Zhanjiang, China.
Department of CardiovasologyThe Affiliated Hospital, Guangdong Medical College, Guangdong, Zhanjiang, China
J Endocrinol. 2016 Aug;230(2):197-214. doi: 10.1530/JOE-16-0004. Epub 2016 Jun 7.
We previously reported that naringin (NRG) protects cardiomyocytes against high glucose (HG)-induced injuries by inhibiting the MAPK pathway. The aim of this study was to test the hypothesis that NRG prevents cardiomyocytes from hyperglycemia-induced insult through the inhibition of the nuclear factor kappa B (NF-κB) pathway and the upregulation of ATP-sensitive K(+) (KATP) channels. Our results showed that exposure of cardiomyocytes to HG for 24h markedly induced injuries, as evidenced by a decrease in cell viability and oxidative stress, and increases in apoptotic cells as well as the dissipation of mitochondrial membrane potential (MMP). These injuries were markedly attenuated by the pretreatment of cells with either NRG or pyrrolidine dithiocarbamate (PDTC) before exposure to HG. Furthermore, in streptozotocin (STZ)-induced diabetic rats and in HG-induced cardiomyocytes, the expression levels of caspase-3, bax and phosphorylated (p)-NF-κB p65 were increased. The increased protein levels were ameliorated by pretreatment with both NRG and PDTC. However, the expression levels of bcl-2 and KATP and superoxide dismutase (SOD) activity were decreased by hyperglycemia; the expression level of Nox4 and the ADP/ATP ratio were increased by hyperglycemia. These hyperglycemia-induced indexes were inhibited by the pretreatment of cardiomyocytes with NRG or PDTC. In addition, in STZ-induced diabetic rats, we also observed that NRG or PDTC contributed to protecting mitochondrial injury and myocardium damage. This study demonstrated that NRG protects cardiomyocytes against hyperglycemia-induced injury by upregulating KATP channels in vitro and inhibiting the NF-κB pathway in vivo and in vitro.
我们之前报道过，柚皮苷（NRG）通过抑制丝裂原活化蛋白激酶（MAPK）途径保护心肌细胞免受高糖（HG）诱导的损伤。本研究的目的是验证以下假设：NRG通过抑制核因子κB（NF-κB）途径和上调ATP敏感性钾（KATP）通道，防止心肌细胞受到高血糖诱导的损伤。我们的结果表明，心肌细胞暴露于HG 24小时会明显诱导损伤，细胞活力降低、氧化应激增加、凋亡细胞增多以及线粒体膜电位（MMP）消散均可证明这一点。在暴露于HG之前，用NRG或吡咯烷二硫代氨基甲酸盐（PDTC）预处理细胞可明显减轻这些损伤。此外，在链脲佐菌素（STZ）诱导的糖尿病大鼠和HG诱导的心肌细胞中，半胱天冬酶-3、bax和磷酸化（p）-NF-κB p65的表达水平升高。NRG和PDTC预处理均可改善蛋白水平的升高。然而，高血糖会降低bcl-2、KATP的表达水平以及超氧化物歧化酶（SOD）活性；高血糖会升高Nox4的表达水平和ADP/ATP比值。用NRG或PDTC预处理心肌细胞可抑制这些高血糖诱导的指标。此外，在STZ诱导的糖尿病大鼠中，我们还观察到NRG或PDTC有助于保护线粒体损伤和心肌损伤。本研究表明，NRG通过在体外上调KATP通道以及在体内和体外抑制NF-κB途径，保护心肌细胞免受高血糖诱导的损伤。
