Metabolic remodeling of cardiomyocytes identified in phosphoinositide-dependent kinase 1-deficient mice
Metabolic remodeling of cardiomyocytes identified in phosphoinositide-dependent kinase 1-deficient mice
复制标题
磷酸肌醇依赖性激酶 1 缺陷型小鼠心肌细胞的代谢重塑
DOI：
10.1042/bcj20190105
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发表时间：
2019-07-15
影响因子：
4.1
通讯作者：
Gao，Hongchang
中科院分区：
文献类型：
--
作者：
Li，Chen;Niu，Yan;Gao，Hongchang
代谢重塑在心力衰竭(HF)的病理生理学中起重要作用。大量研究表明，磷脂酰肌醇依赖的蛋白激酶-1(PDK1)的突变可导致严重的致死性心衰，但PDK1缺失的代谢模式尚不清楚。主成分分析表明，早在4周龄时就有明显的分离，代谢障碍先于Pdk1缺陷小鼠的形态变化。时间轨迹图显示，在Pdk1基因缺陷的小鼠中，紊乱的代谢模式与HF的病理过程有关，而不是与小鼠的年龄有关。代谢谱显示，在Pdk1缺失的小鼠中，醋酸盐、谷氨酸、谷氨酰胺、去磷胆碱水平显著增加。乳酸、丙氨酸、甘氨酸、牛磺酸、胆碱、富马酸、IMP、AMP和ATP水平显著低于对照组。此外，根据海马XF96分析仪的测定，PDK1基因敲除降低了H9C2细胞的耗氧率。提示PDK1缺失型心力衰竭的发病机制可能与代谢紊乱和线粒体活性受损有关。
Metabolic remodeling plays an essential role in the pathophysiology of heart failure (HF). Many studies have shown that the disruption of phosphoinositide-dependent protein kinase-1 (PDK1) caused severe and lethal HF; however, the metabolic pattern of PDK1 deletion remains ambiguous.1H nuclear magnetic resonance-based metabolomics was applied to explore the altered metabolic pattern inPdk1-deficient mice. Principle component analysis showed significant separation as early as 4 weeks of age, and dysfunction of metabolism precedes a morphological change inPdk1-deficient mice. A time trajectory plot indicated that disturbed metabolic patterns were related to the pathological process of the HF inPdk1-deficient mice, rather than the age of mice. Metabolic profiles demonstrated significantly increased levels of acetate, glutamate, glutamine, andO-phosphocholine inPdk1deletion mice. Levels of lactate, alanine, glycine, taurine, choline, fumarate, IMP, AMP, and ATP were significantly decreased compared with controls. Furthermore, PDK1 knockdown decreased the oxygen consumption rate in H9C2 cells as determined using a Seahorse XF96 Analyzer. These findings imply that the disruption of metabolism and impaired mitochondrial activity might be involved in the pathogenesis of HF with PDK1 deletion.