Cytoprotective-selective activated protein C therapy for ischaemic stroke.
Cytoprotective-selective activated protein C therapy for ischaemic stroke.
复制标题
细胞保护选择性激活的蛋白质C疗法用于缺血性中风。
DOI：
10.1160/th14-05-0448
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发表时间：
2014-11
影响因子：
6.7
通讯作者：
Griffin JH
中科院分区：
文献类型：
--
作者：
Mosnier LO;Zlokovic BV;Griffin JH
尽管经过多年的研究和努力将卒中研究转化为临床治疗，但缺血性卒中仍然是死亡、残疾和生活质量下降的主要原因。初级和二级预防措施与提高护理质量相结合，取得了重大进展。然而，在过去的十年中，没有新的药物被批准用于缺血性中风的治疗。许多研究表明，活化蛋白C（APC）在啮齿动物中风模型中的有益作用。除了其天然的抗凝功能外，APC还对许多不同的细胞类型具有多种直接的细胞保护作用，这些细胞类型涉及多种受体，包括蛋白酶激活受体（PAR）1、PAR 3和内皮蛋白C受体（EPCR）。将具有改变的选择性特征的分子工程APC变体应用于啮齿动物中风模型表明，APC的有益作用主要需要其细胞保护活性，而不是其抗凝活性。广泛的基础，临床前和临床研究提供了一个令人信服的理由，基于强有力的证据，翻译APC治疗，导致临床开发的细胞保护选择性APC变体，3 K3 A-APC，缺血性中风。最近鉴定的非经典PAR 1和PAR 3激活APC，产生新的拴系配体能够诱导偏置的细胞保护信号，而不是典型的信号提供了一个机制解释APC介导的PAR激活如何可以选择性地诱导细胞保护信号通路。总的来说，这些范式转变的发现为细胞保护选择性3 K3 A-APC的受体靶点和神经保护的分子机制提供了详细的见解，3 K3 A-APC目前是缺血性卒中临床试验中的生物药物。
Despite years of research and efforts to translate stroke research to clinical therapy, ischemic stroke remains a major cause of death, disability, and diminished quality of life. Primary and secondary preventive measures combined with improved quality of care have made significant progress. However, no novel drug for ischemic stroke therapy has been approved in the past decade. Numerous studies have shown beneficial effects of activated protein C (APC) in rodent stroke models. In addition to its natural anticoagulant functions, APC conveys multiple direct cytoprotective effects on many different cell types that involve multiple receptors including protease activated receptor (PAR) 1, PAR3, and the endothelial protein C receptor (EPCR). Application of molecular engineered APC variants with altered selectivity profiles to rodent stroke models demonstrated that the beneficial effects of APC primarily require its cytoprotective activities but not its anticoagulant activities. Extensive basic, preclinical, and clinical research provided a compelling rationale based on strong evidence for translation of APC therapy that has led to the clinical development of the cytoprotective-selective APC variant, 3K3A-APC, for ischemic stroke. Recent identification of non-canonical PAR1 and PAR3 activation by APC that give rise to novel tethered-ligands capable of inducing biased cytoprotective signaling as opposed to the canonical signaling provides a mechanistic explanation for how APC-mediated PAR activation can selectively induce cytoprotective signaling pathways. Collectively, these paradigm-shifting discoveries provide detailed insights into the receptor targets and the molecular mechanisms for neuroprotection by cytoprotective-selective 3K3A-APC, which is currently a biologic drug in clinical trials for ischemic stroke.