Lipid lowering promotes accumulation of mature smooth muscle cells expressing smooth muscle myosin heavy chain isoforms in rabbit atheroma
Lipid lowering promotes accumulation of mature smooth muscle cells expressing smooth muscle myosin heavy chain isoforms in rabbit atheroma
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DOI：
10.1161/01.res.83.10.1015
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发表时间：
1998-11-16
影响因子：
20.1
通讯作者：
Libby, P
中科院分区：
文献类型：
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作者：
Aikawa, M;Rabkin, E;Libby, P
动脉粥样硬化内膜中的平滑肌细胞（SMC）特征性地不同于动脉介质中的那些，例如，通过SMC分化/成熟标记物如平滑肌肌球蛋白重链同种型（SM 1和SM 2）的表达减少。本研究在33只接受球囊损伤和胆固醇喂养（0.3%）4个月（基线组，n=15）的家兔中检验了降脂促进内膜SMC成熟的假设;其中一些家兔随后转为低胆固醇饮食8个月（低胆固醇组，8个月，n=3）或16个月（低胆固醇组，16个月，n=10）。其余兔继续食用高胆固醇饮食16个月（高组，n=5）。我们通过表达免疫反应性α-平滑肌肌动蛋白、SM 1和SM 2来监测SMC表型。α-肌动蛋白是SMC分化/成熟的早期标志物，而SM 1和SM 2是SMC分化/成熟的晚期标志物。只有完全分化或成熟的SMC表达SM 2。数据报告为通过免疫染色切片的彩色图像分析确定的平滑肌肌球蛋白阳性SMC占据的α-肌动蛋白阳性内膜面积的百分比。SM 1和SM 2水平（正常主动脉中SMC高度表达）（n=5）在基线组和高水平组的主动脉内膜中降低，表明表型较不成熟。相比之下，低（16个月）组的SMI和SM 2增加，表明内膜SMC在降脂后表现出更成熟的表型。电子显微镜也显示存在成熟的内膜SMC与丰富的肌丝。此外，降脂降低了动脉内膜中血小板衍生生长因子-B的水平，这是一种已知抑制平滑肌肌球蛋白表达的因子。这些数据表明，降脂有利于成熟SMC在动脉粥样硬化内膜中的积累，并与血小板源性生长因子-B表达水平降低有关。与基线组和高剂量组相比，低剂量组的内膜SMC也显示基质金属蛋白酶-3和9的表达减少。这些发现揭示了在血管壁水平上降脂的作用，这可能会影响动脉粥样硬化的生物学。
Smooth muscle cells (SMCs) in the atherosclerotic intima characteristically differ from those in the arterial media, for example, by reduced expression of SMC differentiation/maturation markers such as smooth muscle myosin heavy chain isoforms (SM1 and SM2). This study tested the hypothesis that lipid lowering promotes maturation of intimal SMCs in 33 rabbits subjected to balloon injury and cholesterol feeding (0.3%) for 4 months (Baseline group, n=15); some of which then were switched to a low-cholesterol diet for 8 months (Low group at 8 months, n=3) or 16 months (Low group at 16 months, n=10). The remaining rabbits continued to consume a high-cholesterol diet for 16 months (High group, n=5). We monitored SMC phenotype by expression of immunoreactive ct-smooth muscle actin, SM1, and SM2. a-Actin is an early marker, and SM1 and SM2 are late markers for SMC differentiation/maturation. Only fully differentiated or mature SMCs express SM2, Data are reported as the percentage of the alpha-actin-positive intimal area occupied by smooth muscle myosin-positive SMCs determined by color image analysis of immunostained sections. Levels of SM1 and SM2, highly expressed by SMCs in the normal aortic media (n=5) decreased in the aortic intima of the Baseline and High groups, indicating a less mature phenotype. In contrast, SMI and SM2 increased in the Low (16 months) group, indicating that intimal SMCs exhibit a more mature phenotype after lipid lowering. Electron microscopy also showed the presence of mature intimal SMCs with abundant myofilaments. Furthermore, lipid lowering reduced levels of platelet-derived growth factor-B in the arterial intima, a factor known to suppress smooth muscle myosin expression. These data demonstrate that lipid lowering favors accumulation of mature SMCs in the atherosclerotic intima in association with reduced levels of platelet-derived growth factor-B expression. Intimal SMCs in the Low group also displayed reduced expression of matrix metalloproteinases-3 and -9 compared with the Baseline and High groups. These findings shed new light on the effects of lipid lowering at the level of the vascular wall, which may influence the biology of the atheroma.