Essential role of PKC-zeta in normal and angiotensin II-accelerated neointimal growth after vascular injury.
Essential role of PKC-zeta in normal and angiotensin II-accelerated neointimal growth after vascular injury.
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DOI：
10.1152/ajpheart.01363.2005
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发表时间：
2006-10
期刊：
影响因子：
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通讯作者：
J. Parmentier;Chunxiang Zhang;A. Estes;S. Schaefer;K. Malik
中科院分区：
文献类型：
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作者：
J. Parmentier;Chunxiang Zhang;A. Estes;S. Schaefer;K. Malik
采用大鼠颈动脉球囊损伤模型，研究非典型蛋白激酶C（PKC）-zeta在血管紧张素II（ANG II）加速血管内膜损伤后再狭窄中的作用。在第14天，与溶剂相比，受损动脉暴露于ANG II导致广泛的新生内膜增厚（1.9倍）。在存在或不存在ANG II的情况下，用PKC-zeta反义寡核苷酸治疗（而不是乱序寡核苷酸）可减少观察到的新生内膜形成。损伤后早期事件（2天）的检查显示，暴露于ANG II后转移到外膜和中膜的动脉壁血管周围区域的细胞结构增加，PKC-zeta反义寡核苷酸（但非乱序寡核苷酸）阻断了这些事件。第2天的中膜细胞结构与第14天的新生内膜生长程度呈正相关。免疫组织化学分析显示，ANG II加速了损伤后炎症标志物的上调，以及ED 1（+）单核细胞/巨噬细胞从血管周围区域向外膜的浸润。然而，ANG II刺激的中膜细胞结构的增加不依赖于增殖，这些细胞是单核细胞趋化蛋白1（+）/波形蛋白（+），但ED 1（-）/VCAM（-）。PKC-ζ在损伤后降解，并且用PKC-ζ反义抑制其在中膜血管平滑肌细胞或浸润细胞中的新合成减弱中膜细胞性和炎症介质的表达，而不逆转平滑肌细胞去分化。总之，这些数据表明，PKC-zeta通过涉及炎症介质上调的机制在正常和ANG II加速的新生内膜生长中起关键作用，导致血管壁中膜的细胞浸润。
The contribution of atypical protein kinase C (PKC)-zeta to ANG II-accelerated restenosis after endoluminal vascular injury was investigated by using the rat carotid balloon injury model. Exposure of injured arteries to ANG II resulted in an extensive neointimal thickening (1.9 times) compared with vehicle at day 14. Treatment with PKC-zeta antisense, but not scrambled, oligonucleotides reduced neointimal formation observed in the presence or absence of ANG II. Examination of early events (2 days) after injury showed an increase in cellularity in the perivascular area of the artery wall that was transferred to the adventitia and media after exposure to ANG II, events blocked by PKC-zeta antisense, but not scrambled, oligonucleotides. A positive correlation between medial cellularity at day 2 and extent of neointimal growth at day 14 was established. Immunohistochemical analysis showed that upregulation of inflammatory markers after injury, as well as infiltration of ED1(+) monocytes/macrophages from the perivascular area to the adventitia, was accelerated by ANG II. However, ANG II-stimulated medial increase in cellularity was proliferation independent, and these cells were monocyte chemoattractant protein-1(+)/vimentin(+) but ED1(-)/VCAM(-). PKC-zeta is degraded after injury, and inhibition of its neosynthesis in medial vascular smooth muscle cells or in infiltrating cells with PKC-zeta antisense attenuated medial cellularity and expression of inflammation mediators without reversing smooth muscle cell dedifferentiation. Together, these data indicate that PKC-zeta plays a critical role in normal and ANG II-accelerated neointimal growth through a mechanism involving upregulation of inflammatory mediators, leading to cell infiltration in the media of the vascular wall.