糖尿病性心肌病
安普克
医学
链脲佐菌素
糖尿病
内科学
胰岛素
内分泌学
心功能曲线
心肌病
1型糖尿病
AMP活化蛋白激酶
激酶
蛋白激酶A
心力衰竭
生物
细胞生物学
作者
Zhigang Zhang,Yanfang Si,Wenying Hu,Peng-yong Yan,Yongsheng Yu
标识
DOI:10.1016/j.bcp.2021.114574
摘要
Hyperglycaemic memory refers to the damages occurred under early hyperglycaemic environment in organs of diabetic patients persisting after intensive glycaemic control. Mammalian sterile 20-like kinase 1 (Mst1) contributes to the development of diabetic cardiomyopathy. Here, we investigated the role of Mst1 in hyperglycaemic memory and test the effect of XMU-MP-1, a Mst1 inhibitor, on hyperglycaemic memory in hearts. Eight weeks after induction of type 1 diabetes by injection with streptozotocin (STZ) in mice, glycaemic control was obtained by means of insulin treatment and maintained for 4 additional weeks. In the diabetic mice, insulin treatment alone did not reduce phosphorylation of Mst1 or improve cardiac function. Treatment with XMU-MP-1 alone immediately after induction of diabetes for 12 weeks did not improve myocardial function in mice. But treatment with XMU-MP-1 for the later 4 weeks relieved myocardial dysfunction when glycaemic control was obtained by insulin treatment simultaneously. Mst1 deficiency and glycaemic control synergistically improved myocardial function and reduced apoptosis in myocardium of diabetic mice. Mechanistically, when Mst1 was deficient or inhibited by XMU-MP-1, AMPK was activated and mitochondrial dysfunction was attenuated. In vitro, treatment with AMPK activator reversed the detrimental effects of Mst1 overexpression in cultured cardiomyocytes. XMU-MP-1 might thus be envisaged as a complement for insulin treatment against diabetic cardiomyopathy.
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