SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin.
SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin.
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SIRT3通过去乙酰化Frataxin调节心肌细胞凋亡的清除。
DOI：
10.1161/circresaha.123.323160
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发表时间：
2023-09-15
影响因子：
20.1
通讯作者：
Shen, Weili
中科院分区：
文献类型：
--
作者：
Gao, Jing;Huang, Chenglin;Kong, Linghui;Zhou, Wugang;Sun, Mengwei;Wei, Tong;Shen, Weili
效应细胞吞噬作用是巨噬细胞的一种活动，对高血压炎症的消退起着关键作用。巨噬细胞协调胞吐作用和内化凋亡心肌细胞的确切机制尚不清楚。这项研究的目的是确定SIRT3(sirtuin-3)是否在胞吐过程中对凋亡的心肌细胞吞噬和抗炎反应都是必需的。我们产生了髓系SIRT3基因敲除小鼠和携带乙酰化缺陷赖氨酸到精氨酸K189R突变(FXNK189R)的FXN(Frataxin)敲除小鼠。小鼠给予血管紧张素II(Ang II)输注，连续7天。我们分析了体内和体外心肌巨噬细胞的线粒体铁水平、胞吐活性和表型。我们发现，SIRT3缺乏加剧了Ang II诱导的心脏巨噬细胞吞噬受体MerTK(c-Mer酪氨酸激酶)和促炎细胞因子产生的下调，并伴随着线粒体铁稳态的破坏。定量乙酰组分析表明，SIRT3使FXN在189位赖氨酸发生脱乙酰化。Ang II抑制SIRT3活性，增强FXNK189的乙酰化水平。乙酰化的FXN进一步减少了ISCs(铁-硫簇)的合成，导致线粒体铁积累。凋亡心肌细胞吞噬内化增加肌红蛋白含量，衍生铁离子促进线粒体铁超载和脂质过氧化。铁络合剂去铁胺提高了MerTK水平和泡腾作用，从而减弱了促炎巨噬细胞的激活。FXNK189R小鼠表现出巨噬细胞吞噬功能的改善，减少了心脏炎症，并抑制了心脏纤维化。SIRT3-FXN轴具有通过增加巨噬细胞吞噬和抗炎活性来缓解心脏炎症的潜力。
Efferocytosis is an activity of macrophages that is pivotal for the resolution of inflammation in hypertension. The precise mechanism by which macrophages coordinate efferocytosis and internalize apoptotic cardiomyocytes remains unknown. The aim of this study was to determine whether SIRT3 (sirtuin-3) is required for both apoptotic cardiomyocyte engulfment and anti-inflammatory responses during efferocytosis. We generated myeloid SIRT3 knockout mice and FXN (frataxin) knock-in mice carrying an acetylation-defective lysine to arginine K189R mutation (FXNK189R). The mice were given Ang II (angiotensin II) infusion for 7 days. We analyzed cardiac macrophages’ mitochondrial iron levels, efferocytosis activity, and phenotype both in vivo and in vitro. We showed that SIRT3 deficiency exacerbated Ang II–induced downregulation of the efferocytosis receptor MerTK (c-Mer tyrosine kinase) and proinflammatory cytokine production, accompanied by disrupted mitochondrial iron homeostasis in cardiac macrophages. Quantitative acetylome analysis revealed that SIRT3 deacetylated FXN at lysine 189. Ang II attenuated SIRT3 activity and enhanced the acetylation level of FXNK189. Acetylated FXN further reduced the synthesis of ISCs (iron-sulfur clusters), resulting in mitochondrial iron accumulation. Phagocytic internalization of apoptotic cardiomyocytes increased myoglobin content, and derived iron ions promoted mitochondrial iron overload and lipid peroxidation. An iron chelator deferoxamine improved the levels of MerTK and efferocytosis, thereby attenuating proinflammatory macrophage activation. FXNK189R mice showed improved macrophage efferocytosis, reduced cardiac inflammation, and suppressed cardiac fibrosis. The SIRT3-FXN axis has the potential to resolve cardiac inflammation by increasing macrophage efferocytosis and anti-inflammatory activities.
影响因子：
3.7
作者：
Li K;Singh A;Crooks DR;Dai X;Cong Z;Pan L;Ha D;Rouault TA
通讯作者：
Rouault TA