Ca2+/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle.
Ca2+/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle.
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DOI：
10.1016/bs.apha.2016.08.003
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发表时间：
2017-01-01
期刊：
影响因子：
--
通讯作者：
Singer, H A
中科院分区：
文献类型：
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作者：
Saddouk, F Z;Ginnan, R;Singer, H A
钙离子依赖性信号通路是分化的血管平滑肌（VSM）收缩功能的中枢调节因子。此外，Ca 2+信号调节去分化或“合成”表型VSM细胞的VSM基因转录、增殖和迁移。合成表型VSM生长和增生是广泛性血管疾病的标志，包括高血压、动脉粥样硬化、血管成形术后/支架内再狭窄和静脉移植失败。丝氨酸/苏氨酸蛋白激酶Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）是细胞内Ca 2+信号的普遍存在的介导剂。其多功能性、结构复杂性、异构体多样性和剪接变体都是这种蛋白激酶的特征，并使其活性和功能的研究具有挑战性。该激酶具有独特的自动调节机制，新的研究表明，它可以整合Ca 2+和活性氧/氮物质信号。分化的VSM主要表达CaMKII γ和-δ亚型。CaMKII γ亚型表达与分化表型密切相关，一些研究将其功能与调节收缩活性和Ca 2+稳态联系起来。相反，合成表型VSM细胞主要表达CaMKII δ，并且大量证据将其与体外VSM的基因转录、增殖和迁移以及体内血管肥大和增生性重塑的调节联系起来。CaMK Ⅱ δ和γ亚型在体内细胞周期调节、增殖和VSM增生水平上具有相反的功能。血管损伤后的亚型转换是促进血管重塑的关键步骤。最近可用的基因工程小鼠与特定亚型的平滑肌缺失和转基因表达的内源性抑制蛋白（CAMK 2N），使更好地了解CaMKII在VSM中的功能，并应促进未来的研究。
Ca2+-dependent signaling pathways are central regulators of differentiated vascular smooth muscle (VSM) contractile function. In addition, Ca2+ signals regulate VSM gene transcription, proliferation, and migration of dedifferentiated or "synthetic" phenotype VSM cells. Synthetic phenotype VSM growth and hyperplasia are hallmarks of pervasive vascular diseases including hypertension, atherosclerosis, postangioplasty/in-stent restenosis, and vein graft failure. The serine/threonine protein kinase Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous mediator of intracellular Ca2+ signals. Its multifunctional nature, structural complexity, diversity of isoforms, and splice variants all characterize this protein kinase and make study of its activity and function challenging. The kinase has unique autoregulatory mechanisms, and emerging studies suggest that it can function to integrate Ca2+ and reactive oxygen/nitrogen species signaling. Differentiated VSM expresses primarily CaMKIIgamma and -delta isoforms. CaMKIIgamma isoform expression correlates closely with the differentiated phenotype, and some studies link its function to regulation of contractile activity and Ca2+ homeostasis. Conversely, synthetic phenotype VSM cells primarily express CaMKIIdelta and substantial evidence links it to regulation of gene transcription, proliferation, and migration of VSM in vitro, and vascular hypertrophic and hyperplastic remodeling in vivo. CaMKIIdelta and -gamma isoforms have opposing functions at the level of cell cycle regulation, proliferation, and VSM hyperplasia in vivo. Isoform switching following vascular injury is a key step in promoting vascular remodeling. Recent availability of genetically engineered mice with smooth muscle deletion of specific isoforms and transgenics expressing an endogenous inhibitor protein (CAMK2N) has enabled a better understanding of CaMKII function in VSM and should facilitate future studies.