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过高血糖症通过TLR4/c-Src通路激活FGFR1,从而诱导糖尿病患者的炎症性心肌病
Xiong Chen1,2,3, Jinfu Qian4, Shiqi Liang2,4
1Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China.
纤维细胞生长因子受体1 (FGFR1) 通过高葡萄糖激活,通过炎症和纤维化驱动糖尿病心肌病 (DCM). 抑制FGFR1可能在糖尿病中提供心脏保护性益处.
科学领域:
- 生物化学 生化学
- 心脏病学 心脏病学
- 分子生物学分子生物学
背景情况:
- 蛋白氨酸激酶 (RTKs) 在糖尿病并发症中起作用.
- 糖尿病心肌病 (DCM) 病原体需要识别新的治疗点.
研究的目的:
- 调查RTK在DCM开发中的作用.
- 确定涉及高葡萄糖诱导的心脏功能障碍的特定RTK.
主要方法:
- 在糖尿病小鼠心脏中分析RTK酸化.
- 使用初级心肌细胞和H9C2细胞系研究FGFR1激活.
- 使用RNA测序来分析信号通路.
- 产生心肌细胞特异性FGFR1敲击小鼠.
- 在糖尿病小鼠中使用FGFR1抑制剂AZD4547.
主要成果:
- 在糖尿病小鼠心脏中观察到高酸化FGFR1 (p-FGFR1) 水平.
- 高葡萄糖通过收费类受体4 (TLR4) 和c-Src,独立于FGF配体,对FGFR1进行交换.
- 通过MAPKs-NFκB信号传递,FGFR1的激活会诱导促炎反应,导致纤维化和缩.
- 特定于心肌细胞的FGFR1淘汰预防了糖尿病引起的心脏炎症,并保持了心脏功能.
- 治疗AZD4547改善了糖尿病小鼠的心脏炎症,纤维化和功能障碍.
结论:
- FGFR1是DCM病变发生的关键媒介.
- 用AZD4547等抑制剂向FGFR1显示出治疗糖尿病心脏并发症的前景.
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