受体相互作用蛋白激酶1介导坏死样凋亡参与心脑血管损伤及其抑制剂研究进展

Progress in role of RIPK1 in mediation of necroptosis and its inhibitors in cardio-cerebrovascular injuries

坏死样凋亡是一种胱天蛋白酶非依赖性调节性细胞坏死方式,在心肌梗死、脑卒中、药源性心肌病和动脉粥样硬化等损伤相关性心脑疾病的进展中发挥重要作用。受体相互作用蛋白激酶1(RIPK1)是一种参与调节细胞坏死样凋亡的关键蛋白之一。RIPK1介导细胞坏死样凋亡参与(1)心肌损伤,如心肌缺血/再灌注损伤、心力衰竭和药源性心肌毒性等;(2)脑损伤,如脑缺血/再灌注损伤;(3)血管损伤,如动脉粥样硬化引起的血管内皮损伤。靶向抑制RIPK1能减少坏死样凋亡,对心脑血管损伤产生保护作用,表明RIPK1可能是治疗心、脑血管疾病潜在的靶点。目前已有多种类型RIPK1抑制剂,包括靶向RIPK1的D-天冬氨酸-高氨酸-甘氨酸残基中苯丙氨酸向内旋转从而与N端发生相互作用的活性构象的Ⅰ型,靶向RIPK1的D-天冬氨酸-亮氨酸-甘氨酸残基中苯丙氨酸朝外的非活性构象的ATP竞争性Ⅱ型和结合激酶结构域的疏水变构口袋的Ⅲ型,它们通过不同的靶点和机制抑制RIPK1的激酶活性,具有潜在的临床价值。本文综述了RIPK1依赖的坏死样凋亡的发生机制及其在心脑血管疾病中的作用,同时总结了RIPK1抑制剂的研究进展。

Necroptosis is a form of caspase-independent regulated necrosis that plays an important role in the progression of injury-related cardio-cerebrovascular disorders such as myocardial infarction,stroke,drug-induced cardiomyopathy,and atherosclerosis.Receptor-interacting protein kinase 1(RIPK1)is one of the key proteins involved in the regulation of necroptosis.RIPK1-mediated necroptosis is involved in myocardial injury,including myocardial ischemia/reperfusion injury,heart failure and drug-induced myocardial toxicity;RIPK1-mediated necroptosis is also involved in brain injury,such as cerebral ischemia/reperfusion injury;and RIPK1-mediated necroptosis contributes to vascular injury too,such as atherosclerosis-relevant vascular endothelial injury.Targeted inhibition of RIPK1 can reduce necroptosis and exerts a protective effect on cardio-cerebrovascular injury,indicating that RIPK1 may be a potential target for the treatment of cardio-cerebrovascular disorders.There are several types of RIPK1 inhibitors,typeⅠtargets the D-Aspartate-Leucine-Glycine-in conformation,typeⅡtargets the D-Aspartate-Leucine-Glycine-out conformation of RIPK1,which is ATP-competitive,and typeⅢbinds to the hydrophobic back pocket of the kinase domain.They have potential clinical value by inhibiting the kinase activity of RIPK1 through different targets and mechanisms.This review focuses on the mechanism of RIPK1-dependent necroptosis and its role in cardio-cerebrovascular diseases,and summarizes the reports regarding the effects of RIPK1 inhibitors on cardio-cerebrovascular disorders.