University Heart and Vascular Centre Hamburg, Clinic for Cardiology, University Medical Centre Hamburg-Eppendorf, Hamburg, 20246, Germany.
Department of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, 20246, Germany.
Sci Rep. 2020 Mar 16;10(1):4821. doi: 10.1038/s41598-020-61638-3.
L-arginine:glycine amidinotransferase (AGAT) and its metabolites creatine and homoarginine (HA) have been linked to cardiovascular pathologies in both human and murine studies, but the underlying molecular mechanisms are poorly understood. Here, we report the first analysis of heart transcriptome variation using microarrays in an AGAT-deficient (AGAT) mouse model to evaluate AGAT-, creatine- and HA-dependent gene regulation. Our data revealed significant differences of gene expression between AGAT and wild-type (WT) mice, affecting cardiac energy metabolism (Fbp2, Ucp2), cardiac hypertrophy and fibrosis (Nppa, Ctgf), immune response (Fgl2), and the conduction system of the heart (Dsc2, Ehd4, Hcn2, Hcn4, Scn4a, Scn4b). All of these genes being expressed on WT level in creatine-supplemented mice. Using in silico analysis based on the GEO database we found that most of these candidate genes (Ctgf, Dsc2, Fbp2, Fgl2, Hcn2, Nppa) revealed significant alterations in a WT mouse model of myocardial infarction underlining a pathophysiological relationship between AGAT metabolism and cardiovascular disease.
精氨酸-甘氨酸酰胺转移酶（AGAT）及其代谢产物肌酸和同型精氨酸（HA）在人类和小鼠的研究中与心血管病理有关，但潜在的分子机制尚不清楚。在这里，我们使用微阵列首次分析了 AGAT 缺陷（AGAT）小鼠模型中的心脏转录组变化，以评估 AGAT、肌酸和 HA 依赖性基因调控。我们的数据显示，AGAT 和野生型（WT）小鼠之间的基因表达存在显著差异，影响心脏能量代谢（Fbp2，Ucp2）、心脏肥大和纤维化（Nppa，Ctgf）、免疫反应（Fgl2）以及心脏传导系统（Dsc2，Ehd4，Hcn2，Hcn4，Scn4a，Scn4b）。在补充肌酸的小鼠中，所有这些基因在 WT 水平上表达。通过基于 GEO 数据库的计算机分析，我们发现这些候选基因中的大多数（Ctgf，Dsc2，Fbp2，Fgl2，Hcn2，Nppa）在心肌梗死的 WT 小鼠模型中发生了显著改变，这强调了 AGAT 代谢与心血管疾病之间的病理生理关系。
