Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Max Planck Institute for Biology of Ageing, Cologne, Germany.
EMBO Rep. 2019 Apr;20(4). doi: 10.15252/embr.201847407. Epub 2019 Mar 18.
Cardiac dysfunctions dramatically increase with age. Revealing a currently unknown contributor to cardiac ageing, we report the age-dependent, cardiac-specific accumulation of the lysosphingolipid sphinganine (dihydrosphingosine, DHS) as an evolutionarily conserved hallmark of the aged vertebrate heart. Mechanistically, the DHS-derivative sphinganine-1-phosphate (DHS1P) directly inhibits HDAC1, causing an aberrant elevation in histone acetylation and transcription levels, leading to DNA damage. Accordingly, the pharmacological interventions, preventing (i) the accumulation of DHS1P using SPHK2 inhibitors, (ii) the aberrant increase in histone acetylation using histone acetyltransferase (HAT) inhibitors, (iii) the DHS1P-dependent increase in transcription using an RNA polymerase II inhibitor, block DHS-induced DNA damage in human cardiomyocytes. Importantly, an increase in DHS levels in the hearts of healthy young adult mice leads to an impairment in cardiac functionality indicated by a significant reduction in left ventricular fractional shortening and ejection fraction, mimicking the functional deterioration of aged hearts. These molecular and functional defects can be partially prevented using HAT inhibitors. Together, we report an evolutionarily conserved mechanism by which increased DHS levels drive the decline in cardiac health.
心脏功能会随着年龄的增长而显著下降。我们发现了一个目前未知的导致心脏老化的因素，报告了溶血性鞘氨醇（二氢鞘氨醇，DHS）在心脏中的年龄依赖性、特异性积累，这是衰老脊椎动物心脏的一个进化上保守的特征。从机制上讲，DHS 的衍生物神经酰胺-1-磷酸（DHS1P）直接抑制 HDAC1，导致组蛋白乙酰化和转录水平异常升高，从而导致 DNA 损伤。因此，使用 SPHK2 抑制剂（i）预防 DHS1P 积累、使用组蛋白乙酰转移酶（HAT）抑制剂（ii）阻止异常的组蛋白乙酰化增加、使用 RNA 聚合酶 II 抑制剂（iii）阻止 DHS1P 依赖性转录增加，可阻止 DHS 诱导的人心肌细胞中的 DNA 损伤。重要的是，健康年轻成年小鼠心脏中 DHS 水平的升高导致心脏功能受损，左心室缩短分数和射血分数明显降低，模拟衰老心脏的功能恶化。使用 HAT 抑制剂可以部分预防这些分子和功能缺陷。总之，我们报告了一个进化上保守的机制，即 DHS 水平的升高导致心脏健康下降。
