Resveratrol inhibits ferroptosis and decelerates heart failure progression via Sirt1/p53 pathway activation

IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Journal of Cellular and Molecular Medicine Pub Date : 2023-07-24 DOI:10.1111/jcmm.17874
Wei Zhang, Shaohuan Qian, Bi Tang, Pinfang Kang, Heng Zhang, Chao Shi
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引用次数: 3

Abstract

Resveratrol is an organic compound widely studied for its therapeutic uses. We investigated whether resveratrol exerts cardioprotective effects by inhibiting ferroptosis via the Sirt1/p53 pathway. A heart failure model was established by aortic coarctation in Sirt1 knockout mice. The superoxide dismutase (SOD), glutathione (GSH) levels and mitochondrial morphology in murine heart tissues were assessed at different time points to determine the role of ferroptosis in heart failure progression. The cardiac function of mice with heart failure was evaluated by determining the brain natriuretic peptide (BNP) and sST2 concentration and conducting echocardiography. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were transfected with the p53 K382R mutant and Sirt1 interference lentiviral vectors. Immunoprecipitation (IP) experiments were performed to investigate whether Sirt1 influences ferroptosis via p53 K382 acetylation and SLC7A11 expression modulation. Resveratrol improved cardiac function in mice and decelerated ferroptosis and fibrosis progression in heart failure. However, the ability of resveratrol to prevent ferroptosis and treat heart failure was lost after silencing Sirt1. Sirt1 reduced ferroptosis by diminishing the levels of p53 K382 acetylation, reducing the degradation of SLC7A11, and increasing the levels of GSH and glutathione peroxidase 4 (GPX4) in cells. In conclusion, by activating the Sirt1/p53 pathway in heart failure, resveratrol decreased the depletion of SLC7A11, inhibited ferroptosis, and improved cardiac function.

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白藜芦醇通过Sirt1/p53通路激活抑制脱铁性贫血并减缓心力衰竭进展。
白藜芦醇是一种因其治疗用途而被广泛研究的有机化合物。我们研究了白藜芦醇是否通过Sirt1/p53途径抑制脱铁性贫血而发挥心脏保护作用。通过Sirt1基因敲除小鼠主动脉缩窄建立心力衰竭模型。在不同时间点评估小鼠心脏组织中的超氧化物歧化酶(SOD)、谷胱甘肽(GSH)水平和线粒体形态,以确定脱铁性贫血在心力衰竭进展中的作用。通过测定脑钠肽(BNP)和sST2的浓度并进行超声心动图来评估心力衰竭小鼠的心功能。用p53 K382R突变体和Sirt1干扰慢病毒载体转染人诱导多能干细胞衍生的心肌细胞(hiPSC CMs)。进行免疫沉淀(IP)实验以研究Sirt1是否通过p53 K382乙酰化和SLC7A11表达调节来影响脱铁性贫血。白藜芦醇改善了小鼠的心脏功能,减缓了心力衰竭患者的脱铁性贫血和纤维化进展。然而,在沉默Sirt1后,白藜芦醇预防脱铁性贫血和治疗心力衰竭的能力丧失。Sirt1通过降低细胞中p53 K382乙酰化水平、减少SLC7A11的降解以及增加GSH和谷胱甘肽过氧化物酶4(GPX4)水平来减少脱铁性贫血。总之,通过激活心力衰竭中的Sirt1/p53通路,白藜芦醇减少了SLC7A11的耗竭,抑制了脱铁性贫血,并改善了心脏功能。
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来源期刊
CiteScore
10.00
自引率
1.90%
发文量
496
审稿时长
28 weeks
期刊介绍: Bridging physiology and cellular medicine, and molecular biology and molecular therapeutics, Journal of Cellular and Molecular Medicine publishes basic research that furthers our understanding of the cellular and molecular mechanisms of disease and translational studies that convert this knowledge into therapeutic approaches.
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