Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway.
Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway.
复制标题
DOI：
10.1371/journal.pone.0028302
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Christensen G
中科院分区：
文献类型：
--
作者：
Finsen AV;Lunde IG;Sjaastad I;Østli EK;Lyngra M;Jarstadmarken HO;Hasic A;Nygård S;Wilcox-Adelman SA;Goetinck PF;Lyberg T;Skrbic B;Florholmen G;Tønnessen T;Louch WE;Djurovic S;Carlson CR;Christensen G
持续的压力超负荷导致代偿性心肌肥大和随后的心力衰竭，这是发病率和死亡率的主要原因。进一步阐明所涉及的细胞过程对于开发新的治疗策略至关重要。我们已经研究了跨膜Z盘蛋白聚糖syndecan-4的假设，整合素的共受体，连接细胞外基质蛋白的细胞骨架，是一个重要的信号转导在心肌细胞的向心性心肌肥厚的发展过程中压力超负荷。超声心动图、组织化学和心肌细胞大小测量结果显示，syndecan-4−/−小鼠没有出现野生型小鼠中发现的向心性心肌肥大，而是在压力超负荷后出现左心室扩张和功能障碍。蛋白质和基因表达分析显示，减少激活的中央，促肥大的钙调神经磷酸酶核因子的活化T细胞（NFAT）信号通路。来自syndecan-4−/−-NFAT-荧光素酶报告基因小鼠的心肌细胞经历了周期性机械拉伸（一种肥大刺激），与NFAT-荧光素酶对照心肌细胞的5.8倍增加相比，显示出最小的NFAT激活（1.6倍）。因此，多配体蛋白聚糖-4的过表达或引入细胞可渗透膜靶向的多配体蛋白聚糖-4多肽（功能获得）在体外激活NFATc 4。下拉实验证明了直接的细胞内多配体蛋白聚糖-4-钙调磷酸酶相互作用。这种相互作用和NFAT的活化通过多配体蛋白聚糖-4中丝氨酸179（pS179）的去磷酸化而增加。在压力超负荷期间，多配体蛋白聚糖-4的磷酸化减少，并且多配体蛋白聚糖-4、钙调磷酸酶及其共激活剂钙调蛋白之间的关联增加。此外，钙调神经磷酸酶去磷酸化pS179，表明钙调神经磷酸酶调节其自身的结合和激活。最后，由于主动脉瓣狭窄导致心肌肥厚的患者syndecan-4水平增加，pS179降低，这与NFAT激活增加有关。总之，我们的数据表明，syndecan-4是必不可少的代偿性肥大的压力超载的心脏。具体而言，syndecan-4调节心肌细胞中钙调神经磷酸酶-NFAT途径的牵张诱导的激活。因此，我们的数据表明，多配体蛋白聚糖-4的操纵可以提供一种选择，用于钙调神经磷酸酶-NFAT信号转导的治疗调制。
Sustained pressure overload leads to compensatory myocardial hypertrophy and subsequent heart failure, a leading cause of morbidity and mortality. Further unraveling of the cellular processes involved is essential for development of new treatment strategies. We have investigated the hypothesis that the transmembrane Z-disc proteoglycan syndecan-4, a co-receptor for integrins, connecting extracellular matrix proteins to the cytoskeleton, is an important signal transducer in cardiomyocytes during development of concentric myocardial hypertrophy following pressure overload. Echocardiographic, histochemical and cardiomyocyte size measurements showed that syndecan-4−/− mice did not develop concentric myocardial hypertrophy as found in wild-type mice, but rather left ventricular dilatation and dysfunction following pressure overload. Protein and gene expression analyses revealed diminished activation of the central, pro-hypertrophic calcineurin-nuclear factor of activated T-cell (NFAT) signaling pathway. Cardiomyocytes from syndecan-4−/−-NFAT-luciferase reporter mice subjected to cyclic mechanical stretch, a hypertrophic stimulus, showed minimal activation of NFAT (1.6-fold) compared to 5.8-fold increase in NFAT-luciferase control cardiomyocytes. Accordingly, overexpression of syndecan-4 or introducing a cell-permeable membrane-targeted syndecan-4 polypeptide (gain of function) activated NFATc4 in vitro. Pull-down experiments demonstrated a direct intracellular syndecan-4-calcineurin interaction. This interaction and activation of NFAT were increased by dephosphorylation of serine 179 (pS179) in syndecan-4. During pressure overload, phosphorylation of syndecan-4 was decreased, and association between syndecan-4, calcineurin and its co-activator calmodulin increased. Moreover, calcineurin dephosphorylated pS179, indicating that calcineurin regulates its own binding and activation. Finally, patients with hypertrophic myocardium due to aortic stenosis had increased syndecan-4 levels with decreased pS179 which was associated with increased NFAT activation. In conclusion, our data show that syndecan-4 is essential for compensatory hypertrophy in the pressure overloaded heart. Specifically, syndecan-4 regulates stretch-induced activation of the calcineurin-NFAT pathway in cardiomyocytes. Thus, our data suggest that manipulation of syndecan-4 may provide an option for therapeutic modulation of calcineurin-NFAT signaling.
登录
查看更多内容
影响因子：
16
作者：
Aramburu, J;Garcia-Cozar, F;Hogan, PG
通讯作者：
Hogan, PG
影响因子：
20.1
作者：
Matsui, Yutaka;Ikesue, Masahiro;Uede, Toshimitsu
通讯作者：
Uede, Toshimitsu
DOI：
10.1073/pnas.0902639106
发表时间：
2009-12-29
影响因子：
11.1
作者：
Bellin, Robert M.;Kubicek, James D.;LeDuc, Philip R.
通讯作者：
LeDuc, Philip R.
影响因子：
4.1
作者：
Keum, E;Kim, Y;Oh, ES
通讯作者：
Oh, ES
影响因子：
15.9
作者：
Echtermeyer, F;Streit, M;Goetinck, PF
通讯作者：
Goetinck, PF