Barber Melissa N, Kanagasundaram Meetali, Anderson Colin R, Burrell Louise M, Woods Robyn L
Howard Florey Institute, University of Melbourne, Victoria, 3010, Australia.
Cardiovasc Res. 2006 Jul 1;71(1):179-88. doi: 10.1016/j.cardiores.2006.03.019. Epub 2006 Mar 28.
Neutral endopeptidase (NEP, EC 3.4.24.11) metabolises endogenous vasoactive peptides that may protect against atherogenesis. Since NEP is found in the adventitia of arteries, we investigated the anti-atherogenic effects of chronic adventitial NEP inhibition.
Intimal hyperplasia of rabbit carotid arteries was induced by placement of soft, non-occlusive, peri-arterial silastic collars. NEP localisation was studied with autoradiography 7 and 14 days after collar placement. Vascular NEP was inhibited in vivo by local superfusion of one collared carotid artery with Candoxatrilat (50 pmol/h), for 7 days (n = 7). The contralateral collar was filled with saline vehicle. After 7 days, ring segments of collared and normal (proximal to the collar) arteries were obtained and in vitro functional measurements, immunohistochemical determination of the pro-atherogenic factor plasminogen activator inhibitor-1 (PAI-1), localization of macrophages and morphometric analyses were carried out.
Vascular NEP radiolabelled substrate binding, mainly in the media, was increased by approximately 50% after 7 days (n = 5; p < 0.05) and by approximately 300% after 14 days of collar placement (n = 5; p < 0.05). Compared with normal artery segments from the same animal, vehicle-filled collared sections displayed significantly impaired vasorelaxation to acetylcholine (endothelium-independent vasodilatation was preserved), increased PAI-1 immunostaining, macrophage accumulation and intimal thickening. In Candoxatrilat-treated collared arteries, vasorelaxation to acetylcholine was improved, along with reductions in PAI-1 levels, macrophage numbers and intimal area (all p < 0.05).
Enhancing the activity of local, endogenous peptides by adventitial inhibition of vascular NEP may protect against early atherogenesis. This is of particular relevance to using adventitial therapies to prevent intimal hyperplasia leading to restenosis.
中性内肽酶（NEP，EC 3.4.24.11）可代谢内源性血管活性肽，这些肽可能具有抗动脉粥样硬化作用。由于在动脉外膜中发现了NEP，我们研究了慢性外膜NEP抑制的抗动脉粥样硬化作用。
通过放置柔软、非阻塞性的动脉周围硅橡胶套环诱导兔颈动脉内膜增生。在套环放置后7天和14天，用放射自显影术研究NEP的定位。通过对一条套环颈动脉局部灌注坎多曲拉（50 pmol/h）7天（n = 7）在体内抑制血管NEP。对侧套环填充生理盐水。7天后，获取套环动脉和正常（套环近端）动脉的环段，进行体外功能测量、促动脉粥样硬化因子纤溶酶原激活物抑制剂-1（PAI-1）的免疫组化测定、巨噬细胞定位和形态计量分析。
主要在中膜的血管NEP放射性标记底物结合在套环放置7天后增加约50%（n = 5；p < 0.05），在放置14天后增加约300%（n = 5；p < 0.05）。与同一动物的正常动脉段相比，填充生理盐水的套环段对乙酰胆碱的血管舒张功能明显受损（内皮依赖性血管舒张功能保留），PAI-1免疫染色增加、巨噬细胞积聚和内膜增厚。在坎多曲拉治疗的套环动脉中，对乙酰胆碱的血管舒张功能得到改善，同时PAI-1水平、巨噬细胞数量和内膜面积均降低（均p < 0.05）。
通过外膜抑制血管NEP增强局部内源性肽的活性可能预防早期动脉粥样硬化。这对于使用外膜治疗预防导致再狭窄的内膜增生尤为重要。
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