Deficiency of Pdk1 drives heart failure by impairing taurine homeostasis through Slc6a6
Deficiency of Pdk1 drives heart failure by impairing taurine homeostasis through Slc6a6
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DOI：
10.1096/fj.202300272r
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发表时间：
2023-08
期刊：
影响因子：
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通讯作者：
Chen Li;Yi Zhou;Yan Niu;Wenting He;Xinyi Wang;Xi Zhang;Ya-Lian Wu;Wenli Zhang;Liangcai Zha
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文献类型：
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作者：
Chen Li;Yi Zhou;Yan Niu;Wenting He;Xinyi Wang;Xi Zhang;Ya-Lian Wu;Wenli Zhang;Liangcai Zha
3-磷酸肌醇依赖性蛋白激酶-1（Pdk 1）作为一种丝氨酸/苏氨酸蛋白激酶，在多种信号通路中起着关键作用。基因表达综合数据库的分析表明，Pdk 1在心脏病患者中显著下调。蛋白质组学数据集的基因集富集分析确定了Pdk 1直接靶向的凋亡和代谢相关信号通路。以前，我们的研究表明，Pdk 1缺失诱导的代谢变化可能参与心力衰竭的发病机制;然而，潜在的机制仍然难以捉摸。在这里，我们证明，缺乏Pdk 1导致细胞凋亡，氧化损伤和代谢紊乱，在体内和体外。此外，通过1H-NMR进行的代谢组学分析表明，牛磺酸是Pdk 1基因敲除小鼠心脏中的主要差异代谢产物。牛磺酸治疗显著减少活性氧的产生和细胞凋亡，改善心功能，延长Pdk 1缺陷小鼠的生存时间。蛋白质组学筛选确定溶质载体家族6成员6（Slc 6a 6）为改变Pdk 1-表达细胞中牛磺酸水平的下游。一致地，Slc 6a 6在异常Pdk 1表达细胞中挽救了细胞凋亡和氧化损伤。这些研究结果共同表明，Pdk 1缺乏症通过Slc 6a 6触发的牛磺酸稳态紊乱诱导心力衰竭。
3‐Phosphoinositide‐dependent protein kinase‐1 (Pdk1) as a serine/threonine protein kinase plays a critical role in multiple signaling pathways. Analysis of the gene expression omnibus database showed that Pdk1 was significantly downregulated in patients with heart diseases. Gene set enrichment analysis of the proteomics dataset identified apoptotic‐ and metabolism‐related signaling pathways directly targeted by Pdk1. Previously, our research indicated that Pdk1 deletion‐induced metabolic changes might be involved in the pathogenesis of heart failure; however, the underlying mechanism remains elusive. Here, we demonstrated that deficiency of Pdk1 resulted in apoptosis, oxidative damage, and disturbed metabolism, both in vivo and in vitro. Furthermore, profiling of metabonomics by 1H‐NMR demonstrated that taurine was the major differential metabolite in the heart of Pdk1‐knockout mice. Taurine treatment significantly reduced the reactive oxygen species production and apoptosis, improved cardiac function, and prolonged the survival time in Pdk1 deficient mice. Proteomic screening identified solute carrier family 6 member 6 (Slc6a6) as the downstream that altered taurine levels in Pdk1‐expression cells. Consistently, cellular apoptosis and oxidative damage were rescued by Slc6a6 in abnormal Pdk1 expression cells. These findings collectively suggest that Pdk1 deficiency induces heart failure via disturbances in taurine homeostasis, triggered by Slc6a6.