Kunkel George H, Chaturvedi Pankaj, Tyagi Suresh C
Department of Physiology and Biophysics, Health Sciences Centre, A-1216, School of Medicine, University of Louisville, 500, South Preston Street, Louisville, KY, 40202, USA.
Heart Fail Rev. 2015 Nov;20(6):709-19. doi: 10.1007/s10741-015-9501-z.
Although cardiac resuscitation can revive the whole body, the mechanisms are unclear. To this end, we propose that reviving a dead/dysfunctional cardiomyocyte will shed light on resuscitation mechanisms and pave the way to treat cardiac myopathies. The degradation of the myocyte cytoskeleton by the proteasome system which involves calpains, ubiquitin, caspases and matrix metalloproteases is the main focus of this review. The activation of calpains beyond the calpastatin-mediated inhibition due to extensive calcium harbor can lead to titin degradation, damage to the sarcomere and contractile dysfunction. The ubiquitin proteasome system can disturb the protein homeostasis within the cell and generate a dysfunctional myocyte. The matrix metalloproteases disrupt the collagen/elastin ratio and connexins to generate arrhythmias. The concept of cardiac resuscitation stems from protecting the myocyte cytoskeleton and keeping the protein homeostasis intact through management of the degradation machinery. In this regard, proteasome inhibitors for the degradation machinery have an elegant space. Recently exosomes have been identified potentially, as carriers of microRNAs or proteins that can modify the target cells. Exosomes loaded with the inhibitor "cargo" which comprises microRNAs, siRNAs or proteins to inhibit the degradation machinery can be a method of choice for cardiac resuscitation-a process difficult to execute.
尽管心脏复苏能够使全身复苏，但其机制尚不清楚。为此，我们提出复苏死亡或功能失调的心肌细胞将有助于阐明复苏机制，并为治疗心肌病铺平道路。蛋白酶体系统对心肌细胞骨架的降解，涉及钙蛋白酶、泛素、半胱天冬酶和基质金属蛋白酶，是本综述的主要关注点。由于大量钙蓄积导致钙蛋白酶在钙蛋白酶抑制蛋白介导的抑制作用之外被激活，可导致肌联蛋白降解、肌节损伤和收缩功能障碍。泛素蛋白酶体系统可扰乱细胞内的蛋白质稳态，并产生功能失调的心肌细胞。基质金属蛋白酶破坏胶原蛋白/弹性蛋白比例和连接蛋白，从而引发心律失常。心脏复苏的概念源于通过管理降解机制来保护心肌细胞骨架并保持蛋白质稳态完整。在这方面，用于降解机制的蛋白酶体抑制剂具有广阔的应用空间。最近，外泌体已被确定可能作为微小RNA或蛋白质的载体，能够修饰靶细胞。装载有包括微小RNA、小干扰RNA或蛋白质等抑制剂“货物”以抑制降解机制的外泌体，可能成为心脏复苏的一种选择方法——这是一个难以实施的过程。
