Taurine protects against cardiac dysfunction induced by pressure overload through SIRT1-p53 activation
Taurine protects against cardiac dysfunction induced by pressure overload through SIRT1-p53 activation
复制标题
牛磺酸通过 SIRT1-p53 激活防止压力超负荷引起的心脏功能障碍
DOI：
10.1016/j.cbi.2020.108972
复制
发表时间：
2020-02-01
影响因子：
5.1
通讯作者：
Li, Xiaoli
中科院分区：
文献类型：
--
作者：
Liu, Jing;Ai, Yongfei;Li, Xiaoli
背景：心力衰竭（HF）是一种流行性疾病，发病率逐年上升。已有研究表明牛磺酸具有改善心功能的作用。本研究旨在探讨牛磺酸对压力负荷性心力衰竭小鼠心脏的保护作用及其可能的机制。TAC术后给予牛磺酸9周和/或SIRT 1抑制剂EX 527（5 mg/kg/d，每20天1次）。超声心动图显示心脏功能和几何结构。采用荧光麦胚凝集素（WGA）染色和Masson三色染色评估心肌肥厚和纤维化。Western blot和RTPCR分别检测目的蛋白和基因的表达。TUNEL法检测心肌细胞凋亡。检测心肌超氧化物歧化酶（SOD）、丙二醛（MDA）和活性氧（ROS）的含量，评价心肌氧化应激。牛磺酸和NAD +/NADH测定试剂盒测定牛磺酸浓度和NAD +/NADH比值。其机制可能与减轻心肌细胞肥大和纤维化、减轻细胞凋亡和氧化应激有关。同时，牛磺酸增加NAD+/NADH比值，促进SIRT 1表达，抑制p53乙酰化。而SIRT 1抑制剂EX-527可降低NAD+/NADH比值，增加乙酰化p53水平，并可消除牛磺酸对TAC所致小鼠心脏保护作用，增加细胞凋亡和氧化应激。结论：牛磺酸对压力超负荷所致HF的心脏保护作用机制与激活SIRT 1-p53通路有关。
Background: Heart failure (HF) is an epidemic disease with increased incidence annually. It has been reported that taurine can improve cardiac function. This study investigated the cardioprotective effects of taurine in pressure-loaded HF mice and elucidated the possible mechanism.Methods: HF models were established by transverse aortic constriction (TAC). Animals were treated with either taurine for 9 weeks and/or the SIRT1 inhibitor EX527 (5 mg/kg/day, every 2days) after TAC operation. Cardiac function and geometry were revealed by echocardiography. Myocardial hypertrophy and fibrosis were assessed using Fluorescent wheat germ agglutinin (WGA) staining and Masson's trichrome staining. Western blot and RTPCR were performed to elucidate the expression of target proteins and genes respectively. Apoptosis in cardiomyocytes was detected by TUNEL staining. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD) and malonyldialdehyde (MDA) and reactive oxygen species (ROS). Taurine concentrations and NAD+/NADH ratio were determined by taurine and NAD+/NADH assay kit.Results: Taurine notably relieved cardiac dysfunction after TAC. The mechanisms were attributed to reduced myocyte hypertrophy and fibrosis, and alleviated apoptosis and oxidative stress. Meanwhile, taurine increased NAD+/NADH ratio,promoted the expression of SIRT1 and suppressed p53 acetylation. However, EX-527(in-hibitor of SIRT1) decreased NAD+/NADH ratio and increased acetyl-p53 levels, and abolished the cardioprotective effects of taurine on mice subjected to TAC and increased apoptosis and oxidative stress.Conclusion: The mechanism responsible for cardiac-protective effects of taurine in HF induced by pressure overload is associated with the activation of the SIRT1-p53 pathway.