SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1.
SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1.
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DOI：
10.1186/s12933-023-02040-x
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发表时间：
2023-11-28
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
内皮-间充质转化(EndMT)在促进心肌纤维化和加重心功能不全中起重要作用。达帕利嗪(DAPA)是一种钠-葡萄糖连接转运蛋白2(SGLT-2)抑制剂，已被证明可以改善非糖尿病心力衰竭(HF)患者的心功能。然而，DAPA发挥其有益作用的确切机制尚未完全阐明。用异丙肾上腺素(ISO)建立小鼠心力衰竭模型。在体外实验中，我们使用转化生长因子-β-1刺激的人脐静脉内皮细胞(HUVEC)和小鼠主动脉内皮细胞(MAEC)。我们在体内和体外的结果都表明，EndMT发生时SIRT1(NAD+依赖的脱乙酰酶)蛋白表达降低，DAPA治疗可以逆转这一现象。我们发现DAPA对SIRT1抑制的保护作用明显减弱。在机制上，我们观察到DAPA处理减少了SIRT1的磷酸化，这是其泛素化和降解所必需的修饰，这导致了SIRT1的核转位，并促进了它与Notch1的活性胞内结构域(NICD)的结合。这种相互作用导致NICD的去乙酰化和降解，以及随后Notch1信号通路的失活，这有助于改善EndMT。我们的研究表明，DAPA可以减弱ISO诱导的非糖尿病心衰小鼠的EndMT。这种有益的作用是通过SIRT1介导的NICD的脱乙酰化和降解来实现的。我们的发现为DAPA治疗非糖尿病心衰的潜在机制提供了更多的洞察力。网上版载有补充材料，可在10.1186/s12933-023-02040-x查阅。
Endothelial–mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium–glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated. Isoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-β1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs). Both our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT. Our study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF. The online version contains supplementary material available at 10.1186/s12933-023-02040-x.
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影响因子：
64.8
作者：
Guarani V;Deflorian G;Franco CA;Krüger M;Phng LK;Bentley K;Toussaint L;Dequiedt F;Mostoslavsky R;Schmidt MHH;Zimmermann B;Brandes RP;Mione M;Westphal CH;Braun T;Zeiher AM;Gerhardt H;Dimmeler S;Potente M
通讯作者：
Potente M
影响因子：
12.4
作者：
Ma, Li;Zou, Rongjun;Shi, Wanting;Zhou, Na;Chen, Shaoxian;Zhou, Hao;Chen, Xinxin;Wu, Yueheng
通讯作者：
Wu, Yueheng
影响因子：
9.3
作者：
Lee DM;Battson ML;Jarrell DK;Hou S;Ecton KE;Weir TL;Gentile CL
通讯作者：
Gentile CL
影响因子：
5.9
作者：
Lee JY;Lee M;Lee JY;Bae J;Shin E;Lee YH;Lee BW;Kang ES;Cha BS
通讯作者：
Cha BS
SIRT1 对巨噬细胞中 Notch 信号传导的乙酰化依赖性调节影响脓毒症的发展
影响因子：
7.3
作者：
Bai X;He T;Liu Y;Zhang J;Li X;Shi J;Wang K;Han F;Zhang W;Zhang Y;Cai W;Hu D
通讯作者：
Hu D