Takeji Masanobu, Moriyama Toshiki, Oseto Susumu, Kawada Noritaka, Hori Masatsugu, Imai Enyu, Miwa Takeshi
Genome Information Research Center, Research Institute for Microbial Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
J Biol Chem. 2006 Dec 29;281(52):40193-200. doi: 10.1074/jbc.M602182200. Epub 2006 Nov 6.
Myofibroblasts are a major source of proinflammatory cytokines and extracellular matrix in progressive tissue fibrosis leading to chronic organ failure. Myofibroblasts are characterized by de novo expression of smooth muscle alpha-actin (SMalphaA), which correlates with the extent of disease progression, although their exact role is unknown. In vitro cultured myofibroblasts from kidney of SMalphaA knock-out mice demonstrate significantly more prominent cell motility, proliferation, and type-I procollagen expression than those of wild-type myofibroblasts. These pro-fibrotic properties are suppressed by adenovirus-mediated SMalphaA re-expression, accompanied by down-regulation of focal adhesion proteins. In interstitial fibrosis model, tissue fibrosis area, proliferating interstitial cell number, and type-I procollagen expression are enhanced under SMalphaA deficiency. In mesangioproliferative glomerulonephritis model, cell proliferation in the mesangial area is also enhanced in SMalphaA knock-out mice. Adenoviral SMalphaA introduction into renal interstitium obviously ameliorates tissue fibrosis in interstitial fibrosis model. These results indicate that SMalphaA suppresses the pro-fibrotic properties of myofibroblasts, highlighting the significance of smooth muscle-related proteins in moderating chronic organ fibrosis under pathological conditions.
肌成纤维细胞是进行性组织纤维化过程中促炎细胞因子和细胞外基质的主要来源，可导致慢性器官衰竭。肌成纤维细胞的特征是从头表达平滑肌α-肌动蛋白（SMαA），其与疾病进展程度相关，尽管其确切作用尚不清楚。与野生型肌成纤维细胞相比，来自SMαA基因敲除小鼠肾脏的体外培养肌成纤维细胞表现出更显著的细胞运动性、增殖和I型前胶原表达。腺病毒介导的SMαA重新表达可抑制这些促纤维化特性，并伴随粘着斑蛋白的下调。在间质纤维化模型中，SMαA缺乏时组织纤维化面积、增殖性间质细胞数量和I型前胶原表达增加。在系膜增生性肾小球肾炎模型中，SMαA基因敲除小鼠的系膜区细胞增殖也增强。将腺病毒SMαA导入肾间质可明显改善间质纤维化模型中的组织纤维化。这些结果表明，SMαA抑制肌成纤维细胞的促纤维化特性，突出了平滑肌相关蛋白在病理条件下调节慢性器官纤维化中的重要性。
