丹参乙酸镁抗大鼠心肌缺血再灌注细胞程序性坏死的作用及机制

目的探讨丹参乙酸镁(MLB)抗心肌缺血再灌注(IR)细胞程序性坏死的作用及机制。方法采用大鼠左冠状动脉侧支阻断法建立心肌梗死模型。缺血1 h后再灌注3 h,建立心肌IR损伤模型。将大鼠随机分为7组:正常对照组、假手术组、IR组、MLB低剂量(10 mg/kg)+IR组、MLB高剂量(30 mg/kg)+IR组、Necrostatin-1(Nec-1;3 mg/kg)+IR组、溶媒(生理盐水)+IR组(n=6~8)。氯化三苯四唑染色法检测心肌梗死面积,HE染色观察心肌组织形态变化,分光光度法检测血清肌酸激酶(CK)活性,Western blot检测程序性坏死相关蛋白受体相互作用蛋白激酶1(RIPK1)及RIPK3表达水平。结果高剂量MLB可显著减轻IR大鼠心肌梗死面积、CK释放和改善心肌组织结构,伴随抑制RIPK1及RIPK3蛋白表达上调,该作用优于阳性对照药Nec-1。结论 MLB具有抗心肌细胞程序性坏死作用,其机制与抑制RIPK1和RIPK3的蛋白表达有关。     

磷酸甘油酸变位酶5与坏死样凋亡

Necroptosis, or programmed cell death, is a type of cell death with a controllable death signaling pathway and the morphological features similar to necrosis. It is mainly mediated by death receptors or pathogen pattern re-cognition receptors. Among them, tumor necrosis factor receptor 1 (TNFR1)-mediated necroptosis is the most well-studied one. Receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3) are the 2 key kinases involved in the formation of complex I & II and necrosome in the process of necroptosis. Phosphoglycerate mutase 5 (PGAM5), a member of phosphoglycerate mutase gene family, lacks PGAM activity and possesses the phosphatase activity. PGAM5 is anchored in the mitochondrial membrane and is also called mitochondrial phosphoglycerate mutase 5. It has been shown that PGAM5 involves in the formation of necrosome during necroptosis and it is able to accelerate the fission of mitochondria by dephosphorylation of dynamin-related protein 1 (DRP1), thus promoting cell necroptosis.