Goldstein S, Moerman E J, Fujii S, Sobel B E
Department of Medicine, University of Arkansas for Medical Sciences, Little Rock 72205.
J Cell Physiol. 1994 Dec;161(3):571-9. doi: 10.1002/jcp.1041610321.
We previously reported that plasminogen activator inhibitor type-1 (PAI-1) mRNA was present at higher steady-state levels in prematurely senescent fibroblasts derived from a subject with Werner syndrome (WS) compared to early passage (EP) fibroblasts from an age-matched normal subject (Murano et al., 1991, Mol. Cell. Biol. 11:3905-3914). To explore the generally of this phenomenon with respect to chronological age of donor (in vivo aging) and the late-passage (LP) or senescent phase of the fibroblast replicative lifespan, we assayed PAI-1 mRNA in cells and PAI-1 antigen in medium conditioned by 20 normal fibroblast strains at EP and LP and six WS strains during their curtailed replicative lifespans. The lowest accumulations of PAI-1 were found in medium conditioned by fetal and newborn cells with a shallow but progressive rise seen in postnatal cells from normal donors of increasing chronological age. With few exceptions, normal LP fibroblasts showed increased PAI-1 accumulations in medium compared to their EP counterparts. Conditioned medium from four of the six WS strains showed PAI-1 accumulations that were significantly higher than the media of any normal controls at EP and LP. PAI-1 mRNa levels were generally commensurate with the cumulative amount of PAI-1 in the medium but the frequent exceptions indicate that translational and post-translational mechanisms also regulate PAI-1 output. The augmentation in PAI-1 output of fibroblasts as a direct function of chronological age and during in vitro senescence suggests that PAI-1 may play an important role in the reduced capacity for wound healing and the increasing tendency to thrombogenesis and atherogenesis seen during biological aging and in particular in persons with Werner syndrome.
我们之前报道过，与来自年龄匹配的正常受试者的早期传代（EP）成纤维细胞相比，源自一名患有沃纳综合征（WS）受试者的过早衰老成纤维细胞中，纤溶酶原激活物抑制剂1型（PAI-1）mRNA的稳态水平更高（Murano等人，1991年，《分子与细胞生物学》11:3905 - 3914）。为了探究这一现象在供体实际年龄（体内衰老）以及成纤维细胞复制寿命的晚期传代（LP）或衰老阶段方面的普遍性，我们检测了20个正常成纤维细胞株在EP和LP阶段以及6个WS细胞株在其缩短的复制寿命期间，细胞中的PAI-1 mRNA和培养基中的PAI-1抗原。在胎儿和新生儿细胞条件培养基中发现PAI-1的积累量最低，随着实际年龄增加，正常供体的出生后细胞中PAI-1有轻微但逐渐增加的趋势。除少数例外，正常LP成纤维细胞与EP成纤维细胞相比，培养基中PAI-1的积累量增加。6个WS细胞株中的4个的条件培养基显示，PAI-1的积累量显著高于EP和LP阶段任何正常对照的培养基。PAI-1 mRNA水平通常与培养基中PAI-1的累积量相当，但频繁出现的例外情况表明，翻译和翻译后机制也调节PAI-1的输出。成纤维细胞中PAI-1输出量随实际年龄增加以及在体外衰老过程中增加，这表明PAI-1可能在生物衰老期间，尤其是在患有沃纳综合征的个体中，在伤口愈合能力下降以及血栓形成和动脉粥样硬化倾向增加方面发挥重要作用。
