Augmented expression and activity of extracellular matrix-degrading enzymes in regions of low endothelial shear stress colocalize with coronary atheromata with thin fibrous caps in pigs.
Augmented expression and activity of extracellular matrix-degrading enzymes in regions of low endothelial shear stress colocalize with coronary atheromata with thin fibrous caps in pigs.
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DOI：
10.1161/circulationaha.110.970038
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发表时间：
2011-02-15
期刊：
影响因子：
37.8
通讯作者：
Stone PH
中科院分区：
文献类型：
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作者：
Chatzizisis YS;Baker AB;Sukhova GK;Koskinas KC;Papafaklis MI;Beigel R;Jonas M;Coskun AU;Stone BV;Maynard C;Shi GP;Libby P;Feldman CL;Edelman ER;Stone PH
决定冠状动脉中薄冠状动脉粥样硬化局部形成的分子机制仍然未知。本研究验证了低内皮切应力增加基质降解蛋白酶的表达从而促进薄帽动脉粥样硬化形成的假设。血管内超声为基础的，几何正确的三维重建的冠状动脉的12头猪在体内进行23周后开始糖尿病和高脂饮食。用计算流体动力学计算了无斑块的感兴趣亚段（n=142）的局部内皮剪切应力。在第30周，收集冠状动脉（n=31），并确定相同的亚段。评估了所选弹性蛋白酶及其内源性抑制剂的信使RNA和蛋白质表达以及弹性蛋白溶解活性。在第23周具有低的先前内皮剪切应力的亚段在第30周显示内皮覆盖减少、脂质积聚增加和活化炎性细胞的强烈浸润。这些病变显示编码基质金属蛋白酶-2、-9和-12以及组织蛋白酶K和S的信使RNA相对于其内源性抑制剂的表达增加，并且弹性蛋白溶解活性增加。这些酶的表达与内弹性膜断裂的严重程度呈正相关。薄帽动脉粥样硬化发生在内皮剪切力较低的区域，内皮覆盖减少，脂质和炎性细胞聚集，信使RNA表达增强，基质金属蛋白酶和组织蛋白酶的弹性蛋白溶解活性增强，以及严重的内弹性膜断裂。低内皮剪切应力诱导内皮不连续性和活化炎性细胞的积聚，从而增加内膜中弹性蛋白酶的表达和活性，并将其抑制剂的平衡向基质分解转移。我们的研究结果提供了新的洞察机制的区域形成的斑块与薄纤维帽。
The molecular mechanisms that determine the localized formation of thin-capped atheromata in the coronary arteries remain unknown. This study tested the hypothesis that low endothelial shear stress augments the expression of matrix-degrading proteases and thereby promotes the formation of thin-capped atheromata. Intravascular ultrasound–based, geometrically correct 3-dimensional reconstruction of the coronary arteries of 12 swine was performed in vivo 23 weeks after initiation of diabetes mellitus and a hyperlipidemic diet. Local endothelial shear stress was calculated in plaque-free subsegments of interest (n=142) with computational fluid dynamics. At week 30, the coronary arteries (n=31) were harvested and the same subsegments were identified. The messenger RNA and protein expression and elastolytic activity of selected elastases and their endogenous inhibitors were assessed. Subsegments with low preceding endothelial shear stress at week 23 showed reduced endothelial coverage, enhanced lipid accumulation, and intense infiltration of activated inflammatory cells at week 30. These lesions showed increased expression of messenger RNAs encoding matrix metalloproteinase-2, -9, and -12, and cathepsins K and S relative to their endogenous inhibitors and increased elastolytic activity. Expression of these enzymes correlated positively with the severity of internal elastic lamina fragmentation. Thin-capped atheromata developed in regions with lower preceding endothelial shear stress and had reduced endothelial coverage, intense lipid and inflammatory cell accumulation, enhanced messenger RNA expression and elastolytic activity of MMPs and cathepsins, and severe internal elastic lamina fragmentation. Low endothelial shear stress induces endothelial discontinuity and accumulation of activated inflammatory cells, thereby augmenting the expression and activity of elastases in the intima and shifting the balance with their inhibitors toward matrix breakdown. Our results provide new insight into the mechanisms of regional formation of plaques with thin fibrous caps.