p21活化蛋白激酶与心血管疾病:从病理生理学到药物发现(英文)

A new tale of p21 activated protein kinase in the heart:pathophysiology to drug discovery

在全世界范围内,心血管疾病的发病率和死亡率一直都是排在首位的。从心脏信号转导这一新兴领域寻找新疗法的可能性促使人们在过去几十年中对心肌重塑开展了广泛深入研究。本综述将对一种丝氨酸/苏氨酸蛋白激酶——p21活化激酶1(Pak1)——在心脏方面,特别是其心脏保护作用的研究进展作一回顾。我们提出一种Pak1信号转导模型,揭示其特异性影响心脏细胞进程的机制;进而从抗心肌肥厚,抗缺血性损伤以及在生理条件、β-肾上腺素能和肥厚性应激条件下维持心室钙稳态和电生理稳定性的角度探讨它的心脏保护作用。此外,还将通过天然存在的鞘氨醇及其类似物FTY720,以及旨在减少Pak1自抑制而设计的生物活性肽的研究实例来讨论Pak1激活作为心血管疾病新型疗法以及开展药物研发的可能性。

Cardiovascular disease is the number one cause for morbidity and mortality worldwide. Possi-biIities for new therapies in the emerging field of cardiac signalling prompted extensive research on myocardial re-modelling over the past decades. In this review,we as-semble an overview of the recent findings on the multi-functional enzyme,p21-activated kinase 1（ Pak1）,a member of a serine/ threonine protein kinase famiIy in the heart,particularly its cardiac protective effects. We pres-ent a model for Pak1 signaling that provides a mecha-nism for specifically affecting cardiac cellular processes. We discuss its cardiac protective effects such as anti-hy-pertrophy,anti-ischaemic injury and role in maintaining ventricular Ca2＋ homeostasis and electrophysiological stabiIity under physiological, β-adrenergic and hyper-trophic stress conditions.We also discuss the potentials of Pak1 activation by naturally occurring sphingosine and its analogues FTY720,and bioactive peptides designed to diminish Pak1 auto-inhibition as novel thera-peutics for major cardiovascular diseases.