Venkatachalam Kaliyamurthi, Venkatesan Balachandar, Valente Anthony J, Melby Peter C, Nandish Sailesh, Reusch Jane E B, Clark Robert A, Chandrasekar Bysani
Department of Veterans Affairs, South Texas Veterans Health Care System, TX 78229, USA.
J Biol Chem. 2009 May 22;284(21):14414-27. doi: 10.1074/jbc.M809757200. Epub 2009 Apr 1.
WNT1-inducible signaling pathway protein-1 (WISP1), a member of the CYR61/CTGF/Nov family of growth factors, can mediate cell growth, transformation, and survival. Previously we demonstrated that WISP1 is up-regulated in post-infarct heart, stimulates cardiac fibroblast proliferation, and is induced by the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Here we investigated (i) the localization of TNF-alpha and WISP1 in post-infarct heart, (ii) the mechanism of TNF-alpha-mediated WISP1 induction in primary human cardiac fibroblasts (CF), (iii) the role of WISP1 in TNF-alpha-mediated CF proliferation and collagen production, and (iv) the effects of WISP1 on TNF-alpha-mediated cardiomyocyte death. TNF-alpha and WISP1 expressions were increased in the border zones and non-ischemic remote regions of the post-ischemic heart. In CF, TNF-alpha potently induced WISP1 expression in cyclic AMP response element-binding protein (CREB)-dependent manner. TNF-alpha induced CREB phosphorylation in vitro and DNA binding and reporter gene activities in vivo. TNF-alpha induced CREB activation via ERK1/2, and inhibition of ERK1/2 and CREB blunted TNF-alpha-mediated WISP1 induction. Most importantly, WISP1 knockdown attenuated TNF-alpha stimulated collagen production and CF proliferation. Furthermore, WISP1 attenuated TNF-alpha-mediated cardiomyocyte death, thus demonstrating pro-mitogenic and pro-survival effects for WISP1 in myocardial constituent cells. Our results suggest that a TNF-alpha/WISP1 signaling pathway may contribute to post-infarct cardiac remodeling, a condition characterized by fibrosis and progressive cardiomyocyte loss.
WNT1诱导的信号通路蛋白1（WISP1）是CYR61/CTGF/Nov生长因子家族的成员之一，可介导细胞生长、转化和存活。此前我们证明，WISP1在心肌梗死后的心脏中上调，刺激心脏成纤维细胞增殖，并由促炎细胞因子肿瘤坏死因子-α（TNF-α）诱导产生。在此，我们研究了：（i）TNF-α和WISP1在心肌梗死后心脏中的定位；（ii）TNF-α介导的WISP1在原代人心脏成纤维细胞（CF）中诱导产生的机制；（iii）WISP1在TNF-α介导的CF增殖和胶原蛋白产生中的作用；以及（iv）WISP1对TNF-α介导的心肌细胞死亡的影响。TNF-α和WISP1的表达在缺血后心脏的边缘区和非缺血远隔区域增加。在CF中，TNF-α以依赖环磷酸腺苷反应元件结合蛋白（CREB）的方式强烈诱导WISP1表达。TNF-α在体外诱导CREB磷酸化，在体内诱导DNA结合和报告基因活性。TNF-α通过ERK1/2诱导CREB激活，抑制ERK1/2和CREB可减弱TNF-α介导的WISP1诱导。最重要的是，敲低WISP1可减弱TNF-α刺激的胶原蛋白产生和CF增殖。此外，WISP1减弱了TNF-α介导的心肌细胞死亡，从而证明WISP1在心肌组成细胞中具有促有丝分裂和促存活作用。我们的结果表明，TNF-α/WISP1信号通路可能参与心肌梗死后的心脏重塑，这是一种以纤维化和进行性心肌细胞丢失为特征的病症。
