Tomida Shota, Okuhata Hironori, Ishima Tamaki, Nagai Ryozo, Aizawa Kenichi
Department of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Tochigi 329-0498, Japan.
School of Medicine, Faculty of Medicine, Gunma University, Gunma 371-8511, Japan.
Int J Mol Sci. 2025 Aug 14;26(16):7853. doi: 10.3390/ijms26167853.
Pathogenic variants of MYH11, which encode smooth muscle myosin heavy chain 11, have been linked to familial thoracic aortic aneurysms and dissections (FTAAD). However, molecular pathways affected by these mutations have not been well understood. To explore downstream consequences of Myh11 disruption, we analyzed transcriptomic and proteomic profiles of aortas from male Myh11 mice with homozygous deletion of lysine 1256 (K1256) and of wild-type controls. Of 6499 proteins quantified, 1763 were differentially expressed (adjusted < 0.05), including 942 that were downregulated and 821 that were upregulated in mutant aortas. Enrichment analysis of downregulated genes and proteins revealed a consistent reduction in extracellular matrix-related pathways. Among downregulated proteins, we identified tenascin Xb, transforming growth factor β (Tgfb) 2, and Tgfb receptor 1/2, malfunctions of which are linked to connective tissue diseases, such as Ehlers-Danlos and Loeys-Dietz syndromes. Nevertheless, unlike these syndromic diseases, mice with Myh11 pathogenic variants and patients with FTAAD do not exhibit syndromic features, likely reflecting expression of Myh11 restricted to smooth muscle. These results suggest that loss of Myh11 disrupts maintenance of extracellular matrix by SMCs, the loss of which contributes to aortic fragility without affecting other tissues.
编码平滑肌肌球蛋白重链11的MYH11的致病性变异与家族性胸主动脉瘤和夹层（FTAAD）有关。然而，这些突变所影响的分子途径尚未得到很好的理解。为了探究Myh11破坏的下游后果，我们分析了赖氨酸1256（K1256）纯合缺失的雄性Myh11小鼠和野生型对照小鼠主动脉的转录组和蛋白质组谱。在定量的6499种蛋白质中，有1763种差异表达（校正后<0.05），其中942种在突变体主动脉中下调，821种上调。对下调的基因和蛋白质进行的富集分析显示，细胞外基质相关途径持续减少。在下调的蛋白质中，我们鉴定出肌腱蛋白Xb、转化生长因子β（Tgfb）2以及Tgfb受体1/2，它们的功能障碍与诸如埃勒斯-当洛综合征和洛伊氏综合征等结缔组织疾病有关。然而，与这些综合征性疾病不同，具有Myh11致病性变异的小鼠和FTAAD患者并未表现出综合征特征，这可能反映了Myh11的表达仅限于平滑肌。这些结果表明，Myh11的缺失破坏了平滑肌细胞对细胞外基质的维持，其缺失导致主动脉脆弱性增加而不影响其他组织。
