单细胞多模式剖析突出显示,在糖尿病小鼠中,尽管有血糖控制,但大动脉光滑肌细胞持续发生变化
Vinay Singh Tanwar1, Vajir Malek1, Jingyi Wang2
1Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute (V.S.T., V.M., Y.L., N.K.M., M.A., L.L., M.A.R., Z.B.C., R.N.), Beckman Research Institute of City of Hope, Duarte, CA.
Arteriosclerosis, thrombosis, and vascular biology
|February 5, 2026
概括
2型糖尿病导致血管光滑肌细胞 (SMC) 功能障碍,尽管控制葡萄糖,但仍然存在. 药物无法逆转这些糖尿病变化,突出显示了针对代谢记忆的新疗法的需要.
科学领域:
- 心血管生物学 心血管生物学
- 代谢疾病 代谢疾病
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 2型糖尿病加速血管并发症,如高血压和动脉样硬化.
- 血管光滑肌细胞 (SMC) 现型切换是这些并发症的关键驱动因素,在糖尿病中增强.
- 由于先前的高血糖症 (代谢记忆),尽管有血糖控制,但SMC功能障碍可能会持续存在.
研究的目的:
- 调查SMC在2型糖尿病的表型转变期间的转录组和表观组变化.
- 通过单细胞多组学来研究葡萄糖正常化对这些变化的影响.
主要方法:
- 2型糖尿病小鼠 (db/db) 接受了达帕格利弗洛辛 (DAPA) 或载体治疗;对照小鼠 (db/+) 接受了载体治疗.
- 使用单细胞RNA测序,用测序对转化酶可访问的染色质的单细胞检测和空间转录组学分析了大动脉.
- 评估了SMC亚型,基因表达,染色质可访问性和转录因子活性.
主要成果:
- 在糖尿病小鼠中,达帕格利弗洛辛有效控制了血糖和HbA1c.
- 糖尿病诱导的SMC收缩通路减少,纤维化,炎症和内皮功能障碍标志物增加.
- 这些与糖尿病相关的基因表达变化只被DAPA部分逆转,而染色质可访问性变化没有逆转.
- 从收缩到纤维肌细胞样状态的SMC表型过渡与转录因子活性增加有关.
结论:
- 2型糖尿病诱导大动脉SMC中的显著基因表达和染色质可访问性变化,促进表型切换.
- 这些分子变化没有被达帕格利弗洛辛有效地逆转,这表明目前治疗方法的局限性.
- 需要新的治疗策略来解决由高血糖的代谢记忆驱动的持续性SMC功能障碍.
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