Bradykinin Inhibits Oxidative Stress-Induced Cardiomyocytes Senescence via Regulating Redox State
Bradykinin Inhibits Oxidative Stress-Induced Cardiomyocytes Senescence via Regulating Redox State
复制标题
缓激肽通过调节氧化还原状态抑制氧化应激诱导的心肌细胞衰老
DOI：
10.1371/journal.pone.0077034
复制
发表时间：
2013-10-25
期刊：
影响因子：
3.7
通讯作者：
Tu, Ling
中科院分区：
文献类型：
--
作者：
Dong, Ruolan;Xu, Xizhen;Tu, Ling
背景：细胞衰老是许多年龄相关病理过程的中心环节，因此，心肌细胞衰老与许多年龄相关的心血管疾病有关。因此，延缓心肌细胞衰老对控制临床心血管疾病具有重要意义。已有研究表明，缓激肽(BK)对氧化应激诱导的内皮细胞衰老具有保护作用。然而，缓激肽对心肌细胞衰老的影响尚不清楚。本研究探讨了缓激肽对H_2O_2诱导的H9C2细胞衰老的影响。方法和结果：缓激肽以剂量依赖的方式抑制H_2O_2诱导的H9C2细胞的衰老。有趣的是，1nmol/L的BK几乎完全抑制了H_2O_2诱导的衰老细胞数和p21表达的增加。由于H_2O_2通过超氧化物歧化诱导DNA损伤诱导细胞衰老，我们还通过彗星实验观察到，BK能显著减轻H_2O_2诱导的DNA损伤，而且BK处理还能显著抑制H_2O_2诱导的H9C2细胞产生活性氧(ROS)。重要的是，当与缓激肽B2受体拮抗剂HOE-140或eNOS抑制剂N-甲基-L-精氨酸乙酸盐(L-NAME)共同孵育时，缓激肽对H9C2衰老的保护作用被完全阻断。结论：缓激素通过BK B2受体诱导NO释放，上调抗氧化剂铜/锌-超氧化物歧化酶和锰-超氧化物歧化酶的活性和表达，从而抑制氧化应激诱导的心肌细胞氧化应激所致的心肌细胞衰老。
Background: Cell senescence is central to a large body of age related pathology, and accordingly, cardiomyocytes senescence is involved in many age related cardiovascular diseases. In consideration of that, delaying cardiomyocytes senescence is of great importance to control clinical cardiovascular diseases. Previous study indicated that bradykinin (BK) protected endothelial cells from senescence induced by oxidative stress. However, the effects of bradykinin on cardiomyocytes senescence remain to be elucidated. In this study, we investigated the effect of bradykinin on H2O2-induced H9C2 cells senescence.Methods and Results: Bradykinin pretreatment decreased the senescence induced by H2O2 in cultured H9C2 cells in a dose dependent manner. Interestingly, 1 nmol/L of BK almost completely inhibited the increase in senescent cell number and p21 expression induced by H2O2. Since H2O2 induces senescence through superoxide-induced DNA damage, we also observed the DNA damage by comet assay, and BK markedly reduced DNA damage induced by H2O2, and moreover, BK treatment significantly prevented reactive oxygen species (ROS) production in H9C2 cells treated with H2O2. Importantly, when co-incubated with bradykinin B2 receptor antagonist HOE-140 or eNOS inhibitor N-methyl-L-arginine acetate salt (L-NAME), the protective effects of bradykinin on H9C2 senescence were totally blocked. Furthermore, BK administration significantly prevented the increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity characterized by increased ROS generation and gp91 expression and increased translocation of p47 and p67 to the membrane and the decrease in superoxide dismutase (SOD) activity and expression induced by H2O2 in H9C2 cells, which was dependent on BK B2 receptor mediated nitric oxide (NO) release.Conclusions: Bradykinin, acting through BK B2 receptor induced NO release, upregulated antioxidant Cu/Zn-SOD and Mn-SOD activity and expression while downregulating NADPH oxidase activity and subsequently inhibited ROS production, and finally protected against cardiomyocytes senescence induced by oxidative stress.