Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, China.
FASEB J. 2023 Sep;37(9):e23134. doi: 10.1096/fj.202300272R.
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 H-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.
3-磷酸肌醇依赖的蛋白激酶-1（Pdk1）作为一种丝氨酸/苏氨酸蛋白激酶，在多种信号通路中发挥着关键作用。基因表达综合数据库的分析表明，Pdk1 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 Pdk1 直接靶向的凋亡和代谢相关信号通路。先前的研究表明，Pdk1 缺失引起的代谢变化可能参与心力衰竭的发病机制；然而，其潜在机制尚不清楚。在这里，我们证明了 Pdk1 缺失导致体内和体外的细胞凋亡、氧化损伤和代谢紊乱。此外，通过 H-NMR 进行的代谢组学分析表明，牛磺酸是 Pdk1 敲除小鼠心脏中的主要差异代谢物。牛磺酸治疗可显著减少活性氧的产生和凋亡，改善心脏功能，并延长 Pdk1 缺陷小鼠的存活时间。蛋白质组学筛选鉴定溶质载体家族 6 成员 6（Slc6a6）为改变 Pdk1 表达细胞中牛磺酸水平的下游基因。一致地，Slc6a6 可挽救异常 Pdk1 表达细胞中的细胞凋亡和氧化损伤。这些发现共同表明，Pdk1 缺失通过 Slc6a6 引起的牛磺酸稳态失调诱导心力衰竭。
