Frangogiannis N G, Michael L H, Entman M L
Section of Cardiovascular Sciences, Baylor College of Medicine and the De Bakey Heart Center, The Methodist Hospital, Houston TX, USA.
Cardiovasc Res. 2000 Oct;48(1):89-100. doi: 10.1016/s0008-6363(00)00158-9.
The purpose of this study is to examine the cellular content of healing myocardial infarcts and study the phenotypic characteristics of fibroblasts during scar formation utilizing a canine model of coronary occlusion and reperfusion.
Ischemia/Reperfusion experiments were performed in dogs undergoing 1 h of coronary occlusion followed by reperfusion intervals ranging from 5 h to 28 days. Fibrotic and control areas were studied using immunohistochemistry.
The healing ischemic and reperfused myocardium demonstrated significant proliferative activity peaking after 3 to 7 days of reperfusion, predominantly in myofibroblasts. The numbers of proliferating cells decreased during the maturation phase of the scar (PCNA index: 13.7+/-2.25% at 5 days vs. 4.8+/-1.1% at 28 days; P<0.05, n=5). During the proliferative phase of healing (3-7 days) alpha-smooth muscle actin (alpha-SMAc) expression was markedly increased in the fibrotic areas. alpha-SMAc predominantly localized in myofibroblasts which were vimentin positive, smooth muscle myosin, calponin and desmin negative. We examined expression of smooth muscle myosin heavy chain isoforms in myofibroblasts infiltrating the healing areas and found a marked induction of the embryonal isoform of myosin heavy chain (SMemb) in alpha-SMAc positive spindle shaped cells in the border of the scar. Myofibroblasts did not express SM2, a marker for mature smooth muscle cells. In contrast myocardial arterioles were positive for SM2, but did not express SMemb.
Healing myocardial infarcts undergo rapid changes in their content of myofibroblasts. During the proliferative phase fibroblasts undergo phenotypic changes leading to expression of contractile proteins such as alpha-SMAc, and production of SMemb, a marker for dedifferentiated smooth muscle cells. Expression of embryonic isoforms indicates dedifferentiation and allows the myofibroblast pool to serve as a versatile cell population, assuming different phenotypes depending on the physiological needs.
本研究旨在利用犬冠状动脉闭塞和再灌注模型，研究愈合心肌梗死的细胞成分，并探讨瘢痕形成过程中成纤维细胞的表型特征。
对犬进行1小时冠状动脉闭塞，随后再灌注5小时至28天，进行缺血/再灌注实验。采用免疫组织化学方法研究纤维化区域和对照区域。
愈合的缺血再灌注心肌显示出显著的增殖活性，在再灌注3至7天后达到峰值，主要见于肌成纤维细胞。在瘢痕成熟阶段，增殖细胞数量减少（增殖细胞核抗原指数：5天时为13.7±2.25%，28天时为4.8±1.1%；P<0.05，n=5）。在愈合的增殖期（3至7天），纤维化区域α-平滑肌肌动蛋白（α-SMAc）表达明显增加。α-SMAc主要定位于波形蛋白阳性、平滑肌肌球蛋白、钙调蛋白和结蛋白阴性的肌成纤维细胞。我们检测了浸润愈合区域的肌成纤维细胞中平滑肌肌球蛋白重链亚型的表达，发现在瘢痕边缘α-SMAc阳性梭形细胞中，肌球蛋白重链胚胎亚型（SMemb）有明显诱导。肌成纤维细胞不表达成熟平滑肌细胞标志物SM2。相反，心肌小动脉SM2呈阳性，但不表达SMemb。
愈合中的心肌梗死其肌成纤维细胞含量迅速变化。在增殖期，成纤维细胞发生表型变化，导致收缩蛋白如α-SMAc表达，并产生SMemb，这是去分化平滑肌细胞的标志物。胚胎亚型的表达表明去分化，并使肌成纤维细胞群体成为一种多功能细胞群体，可根据生理需要呈现不同表型。
