Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation.
Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation.
复制标题
DOI：
10.3390/ijms22116164
复制
发表时间：
2021-06-07
影响因子：
5.6
通讯作者：
Al Ghouleh I
中科院分区：
文献类型：
--
作者：
Sharifi-Sanjani M;Berman M;Goncharov D;Alhamaydeh M;Avolio TG;Baust J;Chang B;Kobir A;Ross M;St Croix C;Nouraie SM;McTiernan CF;Moravec CS;Goncharova E;Al Ghouleh I
左心室（LV）心力衰竭（HF）是全球范围内重要且不断增加的死亡原因。HF的特征是心肌重塑和过度纤维化。转录共激活因子Yes相关蛋白（雅普）是HIPPO信号通路的下游效应子，是心肌细胞存活的重要因素，但其在人LV HF中的作用尚未完全阐明。在这里，我们报告说，雅普是在HF患者的LV组织升高，并与下调其上游抑制剂HIPPO组件大肿瘤抑制因子1（LATS 1）的激活，以及上调的纤维化标志物结缔组织生长因子（CTGF）。在体外将已建立的促纤维化的TGFβ和缺氧联合应激应用于人心室心脏成纤维细胞，增加了雅普蛋白水平，下调了LATS 1活化，增加了细胞增殖和胶原蛋白I的产生，并降低了核糖体蛋白S6和S6激酶磷酸化，这是mTOR活化的标志，对mTOR和raptor蛋白表达或mTOR或4 E-结合蛋白1（4 EBP 1）（mTOR途径的下游效应物）的磷酸化没有任何显著影响。如先前在各种细胞类型中所报道的，TGFβ/缺氧也增强了心脏成纤维细胞Akt和ERK 1/2磷酸化，这与我们在HF患者LV组织中的观察结果相似。此外，去除雅普可降低TGFβ/缺氧诱导的心脏成纤维细胞增殖和Akt在Ser 473和Thr 308的磷酸化，而对TGFβ/缺氧诱导的ERK 1/2激活或S6和S6激酶活性的降低无任何显著影响。综上所述，这些数据表明，雅普是一种介质，促进人心脏成纤维细胞增殖，并建议其可能的贡献，重塑的LV，打开大门，进一步研究，破译细胞特异性作用的雅普信号在人HF。
Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFβ and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFβ/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFβ/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFβ/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF.
登录
查看更多内容
影响因子：
20.1
作者：
Beauloye, C;Bertrand, L;Hue, L
通讯作者：
Hue, L
影响因子：
15.9
作者：
Nakamura, Tomoki;Colbert, Melissa;Robbins, Jeffrey
通讯作者：
Robbins, Jeffrey
DOI：
10.1016/s0735-1097(01)01792-2
发表时间：
2002-02-20
影响因子：
24
作者：
Norton, GR;Woodiwiss, AJ;Meyer, TE
通讯作者：
Meyer, TE
影响因子：
37.8
作者：
Goncharov DA;Kudryashova TV;Ziai H;Ihida-Stansbury K;DeLisser H;Krymskaya VP;Tuder RM;Kawut SM;Goncharova EA
通讯作者：
Goncharova EA
影响因子：
--
作者：
Hart JR;Vogt PK
通讯作者：
Vogt PK