INSERM UMRS_956; UPMC Univ Paris 06, 91 boulevard de l'Hôpital, Paris Cedex 13, France.
Aging Cell. 2011 Apr;10(2):220-32. doi: 10.1111/j.1474-9726.2010.00661.x. Epub 2010 Dec 29.
Aging is the main risk factor for cardiovascular diseases, but the associated molecular mechanisms are poorly understood. The Wnt signaling pathway was shown to be induced during aging in muscle and in the skin, but the regulation and role of Wnt signaling in the aged vessel have not yet been addressed. While screening for age-related changes in gene expression in the intima/media of human mammary arteries, we observed that the expression of frizzled 4 (Fzd4), a Wnt receptor, and of several targets of the Wnt/β-catenin/TCF signaling pathway [Wnt-inducible secreted protein 1 (WISP1), versican, osteopontin (SPP1), insulin-like growth factor binding protein 2 (IGFBP-2), and p21] were modified with age, suggesting an activation of the Wnt/β-catenin pathway. In contrast, we did not observe any regulation of forkhead transcription factor (FoxO) target genes. Beta-catenin-activating phosphorylation at position Ser675 was increased in aging mammary arteries, confirming the activation of this pathway. We confirmed in vitro that Wnt3a or Wnt1 treatment of human vascular smooth muscle cells (VSMCs) induced β-catenin phosphorylation at Ser675 and WISP1, SPP1, and IGFBP-2 expression. In vitro, Wnt treatment induced proliferation and cyclin D1 expression in VSMC from young (6 weeks old) rats but not in cells from older rats (8 months old), even though low-density lipoprotein receptor-related protein 6 and β-catenin phosphorylation, and β-catenin nuclear translocation demonstrated β-catenin activation in both cell types. Beta-catenin silencing demonstrated that Wnt induction of cyclin D1 expression is β-catenin dependent. Altogether, our data show that the Wnt/β-catenin/TCF pathway is activated in aging human mammary artery cells, but fails to induce the proliferation of aging vascular cells.
衰老是心血管疾病的主要危险因素,但相关的分子机制尚不清楚。研究表明,Wnt 信号通路在肌肉和皮肤衰老过程中被激活,但 Wnt 信号在衰老血管中的调节和作用尚未得到解决。在筛选人乳腺动脉内膜/中膜与年龄相关的基因表达变化时,我们观察到 Wnt 受体卷曲蛋白 4(Fzd4)和 Wnt/β-连环蛋白/TCF 信号通路的几个靶标[Wnt 诱导分泌蛋白 1(WISP1)、蛋白聚糖(versican)、骨桥蛋白(SPP1)、胰岛素样生长因子结合蛋白 2(IGFBP-2)和 p21]的表达随年龄而改变,提示 Wnt/β-连环蛋白途径被激活。相比之下,我们没有观察到叉头转录因子(FoxO)靶基因的任何调节。Wnt3a 或 Wnt1 处理人血管平滑肌细胞(VSMCs)后,β-连环蛋白在 Ser675 位的磷酸化激活增加,证实了该途径的激活。我们在体外证实,Wnt 处理诱导人血管平滑肌细胞(VSMCs)β-连环蛋白在 Ser675 位的磷酸化和 WISP1、SPP1 和 IGFBP-2 的表达。在体外,Wnt 处理诱导年轻(6 周龄)大鼠的 VSMC 增殖和 cyclin D1 表达,但不能诱导老年(8 月龄)大鼠的细胞增殖,尽管低密度脂蛋白受体相关蛋白 6 和β-连环蛋白磷酸化以及β-连环蛋白核转位表明两种细胞类型的β-连环蛋白均被激活。β-连环蛋白沉默表明,Wnt 诱导 cyclin D1 表达依赖于β-连环蛋白。总之,我们的数据表明,Wnt/β-连环蛋白/TCF 途径在衰老的人乳腺动脉细胞中被激活,但未能诱导衰老血管细胞的增殖。