Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan.
Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan.
Int J Mol Sci. 2023 Oct 16;24(20):15213. doi: 10.3390/ijms242015213.
Several genetic defects, including a mutation in myosin heavy chain 11 (), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant () aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca concentration-multiple calcium channel expression and ADP-ribose synthesis-were attenuated in aortas. We suggest that the impairment of the Ca influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection.
几种遗传缺陷，包括肌球蛋白重链 11（）中的突变，据报道可导致家族性胸主动脉瘤和夹层（FTAAD）。我们最近表明，尽管在刺激前不存在主要的病理性表型异常，但缺乏 Myh11 的 K1256 的小鼠在受到血管紧张素 II 刺激时会发生主动脉夹层。在这项研究中，我们使用了一种全面、数据驱动、无偏倚、多组学方法，以发现携带 Myh11 K1256del 突变的小鼠主动脉易发生夹层的转录和代谢潜在变化。转录组的途径分析表明，参与膜转运的基因在纯合突变（）主动脉中下调。此外，通过代谢组学扩展分析表明，两种提高细胞质 Ca 浓度的机制——多种钙通道表达和 ADP-核糖合成——在 主动脉中减弱。我们认为，Ca 流入的损伤会减弱主动脉的收缩，而收缩不足会使主动脉易发生夹层。
