Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma - A potential mechanism of lesion stabilization
Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma - A potential mechanism of lesion stabilization
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DOI：
10.1161/01.cir.97.24.2433
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发表时间：
1998-06-23
期刊：
影响因子：
37.8
通讯作者：
Libby, P
中科院分区：
文献类型：
--
作者：
Aikawa, M;Rabkin, E;Libby, P
背景-富含脂质的动脉粥样硬化斑块中的蛋白水解酶活性可能促进斑块破裂并引发急性冠状动脉综合征，本研究测试了降脂通过降低蛋白水解活性来稳定斑块的假设。方法和结果-我们通过球囊损伤和致动脉粥样硬化饮食（0.3% 胆固醇和 4.7% 椰子油）4 个月，在 33 只兔子身上产生了实验性动脉粥样硬化斑块。当时，有15只兔子被杀死（基线组）。其余动物分为两组：高脂血症组继续食用富含胆固醇的饮食（0.05％至0.2％）16个月以上（n = 5），降脂组食用不添加胆固醇或脂肪的纯化饲料8个月（n = 3）或16个月（n = 10），观察巨噬细胞的积累和间质胶原酶（基质金属蛋白酶-1，MMP-1）的表达。通过免疫染色主动脉标准化切片的定量图像分析来测量病变，基线病变表达高水平的 MMP-1 并含有许多巨噬细胞。这些斑块不稳定的特征在高脂血症组中持续存在，然而，降脂组随着时间的推移，巨噬细胞含量和 MMP-1 免疫反应性逐渐减少。通过 SDS-PAGE 酶谱监测，基线组和高脂血症组的主动脉环具有 MMP-2、MMP-3 或 MMP-9 的明胶分解、酪蛋白分解和弹性蛋白分解活性，降脂组的蛋白水解活性显着下降。通过天狼星红染色测定，与基线或持续高脂血症组相比，降脂组的间质胶原含量增加，表明降脂增强了动脉粥样硬化的纤维骨架。结论-这些结果建立了一种机制，降脂可以通过降低酶的表达和活性来稳定易损斑块，这些酶降解动脉细胞外基质，并通过有利于胶原在纤维中的积累而使动脉粥样硬化不易受到破坏和血栓形成。帽。
Background-Proteolytic enzyme activity in lipid-rich atheroma may promote plaque rupture and precipitate acute coronary syndromes, This study tested the hypothesis that lipid lowering stabilizes plaques by reducing proteolytic activity.Methods and Results-We produced experimental atheroma in 33 rabbits by balloon injury and an atherogenic diet (0.3% cholesterol and 4.7% coconut oil) for 4 months. At that time, 15 rabbits were killed (baseline group). The remaining animals were divided into two groups: a hyperlipemic group continued to consume a cholesterol-enriched diet (0.05% to 0.2%) for 16 more months (n=5) and a lipid-lowering group consumed a purified chow diet with no added cholesterol or fat for 8 (n=3) or 16 months (n=10), Macrophage accumulation and interstitial collagenase (matrix metalloproteinase-1, MMP-1) expression in the lesion were measured by quantitative image analysis of standardized sections of immunostained aortas, Baseline lesions expressed high levels of MMP-1 and contained many macrophages. These features of plaque instability persisted in the hyperlipemic group, However, the lipid-lowering group showed progressive reduction in both macrophage content and MMP-1 immunoreactivity with time. Aortic rings of the baseline and hyperlipemic groups elaborated gelatinolytic, caseinolytic, and elastinolytic activity attributable to MMP-2, MMP-3, or MMP-9, monitored by SDS-PAGE zymography, Proteolytic activity decreased markedly in the lipid-lowering group. Aortic content of interstitial collagen, determined by sirius red staining, increased in the lipid-lowering group compared with the baseline or continued hyperlipemic groups, indicating that lipid lowering reinforced the fibrous skeleton of the atheroma.Conclusions-These results establish a mechanism by which lipid lowering may stabilize vulnerable plaques by reduced expression and activity of enzymes that degrade the arterial extracellular matrix and render atheroma less susceptible to disruption and thrombosis by favoring collagen accumulation in the fibrous cap.