Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, E1354 BST, Pittsburgh, PA, USA.
Department of Neurology, Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, 7016 Biomedical Science Tower-3, 3501 Fifth Ave., Pittsburgh, PA, 15260, USA.
Transl Stroke Res. 2021 Aug;12(4):513-529. doi: 10.1007/s12975-021-00901-9. Epub 2021 Mar 13.
Cerebrovascular disease is the most common life-threatening and debilitating condition that often leads to stroke. The multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key Ca sensor and an important signaling protein in a variety of biological systems within the brain, heart, and vasculature. In the brain, past stroke-related studies have been mainly focused on the role of CaMKII in ischemic stroke in neurons and established CaMKII as a major mediator of neuronal cell death induced by glutamate excitotoxicity and oxidative stress following ischemic stroke. However, with growing understanding of the importance of neurovascular interactions in cerebrovascular diseases, there are clearly gaps in our understanding of how CaMKII functions in the complex neurovascular biological processes and its contributions to cerebrovascular diseases. Additionally, emerging evidence demonstrates novel regulatory mechanisms of CaMKII and potential roles of the less-studied CaMKII isoforms in the ischemic brain, which has sparked renewed interests in this dynamic kinase family. This review discusses past findings and emerging evidence on CaMKII in several major cerebrovascular dysfunctions including ischemic stroke, hemorrhagic stroke, and vascular dementia, focusing on the unique roles played by CaMKII in the underlying biological processes of neuronal cell death, neuroinflammation, and endothelial barrier dysfunction triggered by stroke. We also highlight exciting new findings, promising therapeutic agents, and future perspectives for CaMKII in cerebrovascular systems.
脑血管疾病是最常见的危及生命和使人丧失能力的疾病，通常会导致中风。多功能钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）是大脑、心脏和血管中各种生物系统内的关键钙传感器和重要信号蛋白。在大脑中，过去与中风相关的研究主要集中在 CaMKII 在神经元缺血性中风中的作用，并确立了 CaMKII 作为谷氨酸兴奋性毒性和缺血性中风后氧化应激诱导的神经元细胞死亡的主要介导物。然而，随着对神经血管相互作用在脑血管疾病中的重要性认识的提高，我们对 CaMKII 在复杂的神经血管生物学过程中的功能以及其对脑血管疾病的贡献的理解显然存在差距。此外，新出现的证据表明 CaMKII 的新调节机制和在缺血性大脑中较少研究的 CaMKII 同工型的潜在作用，这激发了人们对这个动态激酶家族的新兴趣。本综述讨论了过去关于 CaMKII 在几种主要脑血管功能障碍（包括缺血性中风、出血性中风和血管性痴呆）中的发现和新出现的证据，重点讨论了 CaMKII 在中风引发的神经元细胞死亡、神经炎症和内皮屏障功能障碍的潜在生物学过程中发挥的独特作用。我们还强调了 CaMKII 在脑血管系统中的令人兴奋的新发现、有前途的治疗剂和未来展望。
