Qian Jian-Yong, Haruno Akihiro, Asada Yujiro, Nishida Takahiro, Saito Yasushi, Matsuda Takehisa, Ueno Hikaru
Department of Biochemistry and Molecular Pathophysiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Circ Res. 2002 Nov 29;91(11):1063-9. doi: 10.1161/01.res.0000043631.25915.e6.
We previously observed that adenovirus-mediated expression of C-type natriuretic peptide (CNP) markedly inhibits neointima formation after balloon injury in rat carotid arteries, suggesting that CNP has multiple effects over its modest inhibitory effect on cellular proliferation. We hypothesized that local expression of CNP might have antithrombotic and antiinflammatory effects. Balloon-injured rabbit carotid arteries were infected with an adenovirus expressing human CNP (AdCNP), human tissue factor pathway inhibitor (AdTFPI), or bacterial beta-galactosidase (AdLacZ) or infused with saline. Seven days later, shear stress-induced thrombosis was evaluated by cyclic flow variation (CFV), reflecting recurrent cycles of thrombus formation and dislodgment. CFV was observed in all AdLacZ-infected and saline-infused arteries but not in arteries infected with AdCNP or AdTFPI even in the presence of epinephrine. Injury increased the expressions of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and infiltration of macrophages. However, these effects were markedly reduced in AdCNP-treated arteries but not in AdTFPI-infected ones. In AdCNP-infected arteries, injury-induced expression of inducible NO synthase (iNOS) was enhanced, leading to increased NO generation. Interestingly, when the enhanced NO production was inhibited, neither inhibitory effect was observed, and suppression of neointima formation by CNP was canceled. Our study demonstrates that overexpression of CNP shows antithrombotic and antiinflammatory effects and reduces neointima formation mainly through enhanced NO production.
我们先前观察到，腺病毒介导的C型利钠肽（CNP）表达可显著抑制大鼠颈动脉球囊损伤后的内膜增生，这表明CNP除了对细胞增殖有适度抑制作用外，还具有多种效应。我们推测CNP的局部表达可能具有抗血栓形成和抗炎作用。将表达人CNP（AdCNP）、人组织因子途径抑制剂（AdTFPI）或细菌β-半乳糖苷酶（AdLacZ）的腺病毒感染兔颈动脉球囊损伤部位，或灌注生理盐水。7天后，通过循环血流变化（CFV）评估剪切应力诱导的血栓形成，CFV反映血栓形成和脱落的反复循环。在所有感染AdLacZ和灌注生理盐水的动脉中均观察到CFV，但在感染AdCNP或AdTFPI的动脉中未观察到，即使存在肾上腺素时也是如此。损伤增加了细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）的表达以及巨噬细胞的浸润。然而，这些效应在AdCNP处理的动脉中明显降低，但在AdTFPI感染的动脉中未降低。在感染AdCNP的动脉中，损伤诱导的诱导型一氧化氮合酶（iNOS）表达增强，导致一氧化氮生成增加。有趣的是，当增强的一氧化氮生成被抑制时，未观察到任何抑制作用，并且CNP对内膜增生的抑制作用被消除。我们的研究表明，CNP的过表达具有抗血栓形成和抗炎作用，并且主要通过增强一氧化氮生成来减少内膜增生。
