a Department of Pharmacy, The First Affiliated Hospital, Nanchang University, Nanchang, China.
b Jiangxi Provincial Institute of Hypertension, The First Affiliated Hospital, Nanchang University , Nanchang , China.
Toxicol Mech Methods. 2019 Jun;29(5):344-354. doi: 10.1080/15376516.2018.1564948. Epub 2019 Feb 18.
Cardiotoxicity limits the clinical applications of doxorubicin (Dox), which mechanism might be excess generation of intracellular ROS. Quercetin (Que) is a flavonoid that possesses anti-oxidative activities, exerts myocardial protection. We hypothesized that the cardioprotection against Dox injury of Que involved 14-3-3γ, and mitochondria. To investigate the hypothesis, we treated primary cardiomyocytes with Dox and determined the effects of Que pretreatment with or without 14-3-3γ knockdown. We analyzed various cellular and molecular indexes. Our data showed that Que attenuated Dox-induced toxicity in cardiomyocytes by upregulating 14-3-3γ expression. Que pretreatment increased cell viability, SOD, catalase, and GPx activities, GSH levels, MMP and the GSH/GSSG ratio; decreased LDH and caspase-3 activities, MDA and ROS levels, mPTP opening and the percentage of apoptotic cells. However, Que's cardioprotection were attenuated by knocking down 14-3-3γ expression using pAD/14-3-3γ-shRNA. In conclusion, Que protects cardiomyocytes against Dox injury by suppressing oxidative stress and improving mitochondrial function via 14-3-3γ.
蒽环类药物（Dox）的心脏毒性限制了其临床应用，其机制可能是细胞内 ROS 的过度产生。槲皮素（Que）是一种具有抗氧化活性的类黄酮，具有心肌保护作用。我们假设 Que 对 Dox 损伤的心脏保护作用涉及 14-3-3γ 和线粒体。为了验证这一假说，我们用 Dox 处理原代心肌细胞，并确定 Que 预处理是否与 14-3-3γ 敲低有关。我们分析了各种细胞和分子指标。我们的数据表明，Que 通过上调 14-3-3γ 的表达来减轻 Dox 诱导的心肌细胞毒性。Que 预处理可增加细胞活力、SOD、过氧化氢酶和 GPx 活性、GSH 水平、MMP 和 GSH/GSSG 比值；降低 LDH 和 caspase-3 活性、MDA 和 ROS 水平、mPTP 开放和凋亡细胞的百分比。然而，使用 pAD/14-3-3γ-shRNA 敲低 14-3-3γ 的表达后，Que 的心脏保护作用被减弱。总之，Que 通过抑制氧化应激和改善线粒体功能来保护心肌细胞免受 Dox 损伤，这一过程涉及 14-3-3γ。
