Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction.
Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction.
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心肌梗死后乳酸盐通过Snail 1乳糖化促进内皮细胞向间质细胞转化
DOI：
10.1126/sciadv.adc9465
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发表时间：
2023-02-03
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
高乳酸水平与心脏病发作患者的预后和死亡率呈正相关。内皮-间质转化（EndoMT）在心脏纤维化中起重要作用。在这里，我们报告，乳酸发挥了以前未知的功能，增加心脏纤维化和加剧心功能不全，促进心肌梗死（MI）后内皮MT。用乳酸盐处理内皮细胞破坏内皮细胞功能，并通过激活TGF-β/Smad 2途径诱导缺氧后的间充质样功能。从机制上讲，乳酸通过乳酸转运蛋白单羧酸转运蛋白（MCT）依赖性信号转导诱导CBP/p300和Snail 1之间的结合，导致Snail 1（一种TGF-β转录因子）的乳酸化。抑制Snail 1减少了缺氧/MI后乳酸诱导的EndoMT和TGF-β/Smad 2活化。MCT抑制剂CHC减轻乳酸盐诱导的EndoMT和Snail 1乳酸化。MCT 1的沉默损害了MI后乳酸盐促进的心功能不全和EndoMT我们的结论是，乳酸作为一个重要的分子，上调心肌梗死后通过诱导Snail 1乳酸化心脏EndoMT。乳酸盐会促进心脏病发作时的纤维化。
High levels of lactate are positively associated with the prognosis and mortality in patients with heart attack. Endothelial-to-mesenchymal transition (EndoMT) plays an important role in cardiac fibrosis. Here, we report that lactate exerts a previously unknown function that increases cardiac fibrosis and exacerbates cardiac dysfunction by promoting EndoMT following myocardial infarction (MI). Treatment of endothelial cells with lactate disrupts endothelial cell function and induces mesenchymal-like function following hypoxia by activating the TGF-β/Smad2 pathway. Mechanistically, lactate induces an association between CBP/p300 and Snail1, leading to lactylation of Snail1, a TGF-β transcription factor, through lactate transporter monocarboxylate transporter (MCT)–dependent signaling. Inhibiting Snail1 diminishes lactate-induced EndoMT and TGF-β/Smad2 activation after hypoxia/MI. The MCT inhibitor CHC mitigates lactate-induced EndoMT and Snail1 lactylation. Silence of MCT1 compromises lactate-promoted cardiac dysfunction and EndoMT after MI. We conclude that lactate acts as an important molecule that up-regulates cardiac EndoMT after MI via induction of Snail1 lactylation. Lactate promotes fibrosis in heart attacks.
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