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EGFR/IGF1R信号调节过度缩性心肌病的放松

Sila Algül¹, Maike Schuldt¹, Emmy Manders^1,2

¹Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (S.A., M.S., E.M., V.J., M.H., J.v.d.V., D.W.D.K.).

Circulation research

|July 21, 2023

概括

研究人员选了激酶抑制剂,以寻找新的方法来改善高性心肌病 (HCM) 的心脏放松. 他们确定EGFR/IGF1R信号传导是开发治疗方法治疗HCM患者减弱放松的有希望的目标.

科学领域:

心脏病学心脏病学
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

扩张性功能障碍是心力衰竭的关键特征,其中有保存的射出分数和高性心肌病 (HCM).
改善心脏放松的有效疗法是有限的,这是由于对心肌细胞放松调节器的不完全理解.
假设激酶失调有助于在HCM中减弱放松.

研究的目的:

通过对激酶抑制剂的高通量查,识别心肌细胞放松的新型调节剂.
为了研究HCM患者的心肌中激酶失调.
验证HCM中心脏放松受损的潜在治疗标.

主要方法:

在孤立的成年野生类型小鼠心肌细胞中选了157种激酶抑制剂,以确定阳性卢西特洛普 (改善放松的药物).
在HCM患者的心肌上进行了蛋白组学和推断酶活性分析.
从MYBPC3突变诱导的HCM小鼠模型中验证了心肌细胞中已识别的激酶抑制剂.

主要成果:

确定了21种新型阳性卢西特罗普,聚合到细胞循环,EGFR/IGF1R和Akt信号通路中.
在HCM患者的心肌中,EGFR/IGF1R通路蛋白的激活增加.
三种EGFR/IGF1R通路抑制剂改善了HCM心肌细胞的放松.

结论:

证明了对心肌细胞放松调节器进行查的可行性.
EGFR/IGF1R,Akt,细胞循环和FoxO信号通路中的激酶调节心肌细胞放松和收缩.
抑制EGFR/IGF1R信号传递是一种有前途的治疗策略,用于HCM中减弱放松.

关键词:

心肌病,高性心肌病,高性心肌病.皮肤上生长因子受体.高通量选的高通量选类似胰岛素的生长因子受体.左心室透静功能障碍左心室透静功能障碍肌细胞,心脏细胞.蛋白质激酶抑制剂蛋白质激酶抑制剂

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