Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders.
Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders.
复制标题
DOI：
10.1016/bs.apha.2016.06.002
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Khalil RA
中科院分区：
文献类型：
--
作者：
Ringvold HC;Khalil RA
血管平滑肌(VSM)在维持血管张力方面起着重要作用。除了钙离子依赖的肌球蛋白轻链(MLC)的磷酸化外，蛋白激酶C(PKC)是VSM功能的主要调节因子。蛋白激酶C是一类传统的钙依赖性α，β、γ、新型钙非依赖性δ，ε，θ、η、非典型ξ和ι/λ亚型。非活性的PKC主要是胞浆的，激活后经历磷酸化、成熟和移位到表膜、核、内质网和其他细胞器；这个过程由支架蛋白(如支架蛋白)促进。活化的PKC可磷酸化不同的底物，包括离子通道、泵和核蛋白。PKC还使CPI-17磷酸化，从而抑制MLC磷酸酶，增加MLC磷酸化，增强VSM收缩。PKC还可以启动一连串的蛋白激酶，导致肌动蛋白结合蛋白Calponin和caldesmon的磷酸化，增加肌动蛋白-肌球蛋白的相互作用和VSM收缩。PKC活性升高与血管病变有关，包括缺血再灌注损伤、冠状动脉疾病、高血压和糖尿病血管病变。PKC抑制剂可以检测PKC在不同系统中的作用，并可以减轻血管疾病中PKC的过度活动。第一代PKC抑制剂，如星形孢子素和白屈菜红碱，并不是非常特异的。异构体特异性的PKC抑制剂，如Ruboxistaurin，已经在临床试验中进行了测试。靶向递送PKC伪底物抑制肽和PKC siRNA可能有助于局部血管疾病的治疗。对PKC及其在VSM中作用的进一步研究将有助于设计针对血管疾病中PKC的实验有效和临床安全的异构体特异性PKC调节剂。
Vascular smooth muscle (VSM) plays an important role in maintaining vascular tone. In addition to Ca2+-dependent myosin light chain (MLC) phosphorylation, protein kinase C (PKC) is a major regulator of VSM function. PKC is a family of conventional Ca2+-dependent α, β, and γ, novel Ca2+-independent δ, ε, θ, and η, and atypical ξ, and ι/λ isoforms. Inactive PKC is mainly cytosolic, and upon activation it undergoes phosphorylation, maturation and translocation to the surface membrane, the nucleus, endoplasmic reticulum, and other cell organelles; a process facilitated by scaffold proteins such as RACKs. Activated PKC phosphorylates different substrates including ion channels, pumps and nuclear proteins. PKC also phosphorylates CPI-17 leading to inhibition of MLC phosphatase, increased MLC phosphorylation and enhanced VSM contraction. PKC could also initiate a cascade of protein kinases leading to phosphorylation of the actin-binding proteins calponin and caldesmon, increased actin-myosin interaction and VSM contraction. Increased PKC activity has been associated with vascular disorders including ischemia-reperfusion injury, coronary artery disease, hypertension, and diabetic vasculopathy. PKC inhibitors could test the role of PKC in different systems, and could reduce PKC hyperactivity in vascular disorders. First generation PKC inhibitors such as staurosporine and chelerythrine are not very specific. Isoform-specific PKC inhibitors such as ruboxistaurin have been tested in clinical trials. Target-delivery of PKC pseudosubstrate inhibitory peptides and PKC siRNA may be useful in localized vascular disease. Further studies of PKC and its role in VSM should help design isoform-specific PKC modulators that are experimentally potent and clinically safe to target PKC in vascular disease.