Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice
Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice
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DOI：
10.1161/01.atv.0000147126.99529.0a
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发表时间：
2004-12-01
影响因子：
8.7
通讯作者：
Biessen, EAL
中科院分区：
文献类型：
--
作者：
de Nooijer, R;von der Thüsen, JH;Biessen, EAL
目的 - 尽管 IL-18 与动脉粥样硬化病变的发展有关，但对其在晚期动脉粥样硬化斑块中的作用知之甚少。本研究旨在评估 IL-18 过表达对先前存在斑块稳定性的影响。方法和结果 - 通过放置血管周围项圈，在载脂蛋白 E (apoE) 缺陷小鼠 (n = 32) 的颈动脉中引发动脉粥样硬化病变。手术后 5 周静脉注射腺病毒载体可实现 IL-18 的过度表达。转导两周后，对病变进行组织学分析，包括斑块形态和组成或通过实时聚合酶链反应。组间未检测到斑块大小差异。在广告中。 IL-18治疗组中，62%的病变表现出脆弱的形态，甚至斑块内出血，而对照组中只有24%（P = 0.037）。一致认为，IL-18 过度表达使内膜胶原蛋白减少 44%（P < 0.003），帽核比减少 41%（P < 0.002）。尽管IL-18不影响胶原合成相关基因的表达，但在体外发现它增强血管平滑肌细胞的溶胶原活性，这表明胶原含量低是由于基质降解而不是合成减少所致。结论 - 全身性IL-18过度表达显着降低内膜胶原含量和帽厚度，导致易损斑块 形态学。
Objective - Although IL-18 has been implicated in atherosclerotic lesion development, little is known about its role in advanced atherosclerotic plaques. This study aims to assess the effect of IL-18 overexpression on the stability of preexisting plaques.Methods and Results - Atherosclerotic lesions were elicited in carotid arteries of apolipoprotein E ( apoE)- deficient mice (n = 32) by placement of a perivascular collar. Overexpression of IL-18 was effected by intravenous injection of an adenoviral vector 5 weeks after surgery. Two weeks after transduction, lesions were analyzed histologically with regard to plaque morphology and composition or by real-time polymerase chain reaction. No difference in plaque size was detected between groups. In the Ad. IL-18-treated group, 62% of lesions displayed a vulnerable morphology or even intraplaque hemorrhage as compared with only 24% in the controls (P = 0.037). In agreement, IL-18 overexpression reduced intimal collagen by 44% (P < 0.003) and cap-to-core ratio by 41% (P < 0.002). Although IL-18 did not affect the expression of collagen synthesis-related genes, it was found to enhance the collagenolytic activity of vascular smooth muscle cells in vitro, suggesting that the low collagen content is attributable to matrix degradation rather than to decreased synthesis.Conclusion - Systemic IL-18 overexpression markedly decreases intimal collagen content and cap thickness, leading to a vulnerable plaque morphology.