TGF-β1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation
TGF-β1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation
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DOI：
10.1016/j.yjmcc.2005.06.016
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发表时间：
2005-10-01
影响因子：
5
通讯作者：
Park, SI
中科院分区：
文献类型：
--
作者：
Lim, JY;Park, SJ;Park, SI
一些报告表明 TAK1-MKK3/6-p38MAPK 信号轴对于 TGF-β 相关的心脏肥大很重要。尽管如此，外源性TGF-β对心脏肥大和相关信号传导机制的影响尚未得到直接证实。此外，涉及心脏肥大的信号传导机制（TAK1上游和p38MAPK下游）的作用仍不清楚。在这项研究中，我们研究了蛋白激酶 C 和激活转录因子 2 在培养的新生大鼠心室心肌细胞中 TGF-β 1 诱导的心脏肥大反应中的潜在参与。 TGF-β1治疗导致β-肌球蛋白重链、心房钠尿因子和脑钠尿肽的mRNA表达或启动子活性上调，并增加肌细胞蛋白质含量、细胞大小和肌节组织。这些都是心脏肥大的特征。研究发现 PKC 参与整个信号系统，并且表明它通过介导上游 TAK1 激活并导致 ATF-2 激活而发挥作用。 PKC 依赖性 ATF-2 激活被证明参与 TGF-β 1 诱导的心脏肥大反应。 PKC 抑制剂 GO6976 和 GF109203X 完全阻断 TGF-β 1 诱导的 TAK1 激酶活性以及随后的下游信号通路（包括 ATF-2 磷酸化），从而抑制 ATF-2 转录活性。这种抑制作用反映在心脏肥大反应中，例如抑制 β-MHC 基因诱导和 ANF 启动子活性。我们的结果表明，PKC 参与细胞培养系统中 TGF-β1 诱导的心脏肥大反应，并且 ATF-2 激活发挥了作用。 (c) 2005 Elsevier Ltd. 保留所有权利。
Several reports have suggested that the TAK1-MKK3/6-p38MAPK signaling axis is important for TGF-beta-related cardiac hypertrophy. Despite this, the effects of exogenous TGF-beta on cardiac hypertrophy and associated signaling mechanisms have not been demonstrated directly. Moreover, the roles of the signaling mechanisms involved in cardiac hypertrophy (TAK1 upstream and p38MAPK downstream) remain unclear. In this study, we investigated the potential involvement of protein kinase C and activating transcription factor-2 in TGF-beta 1-induced cardiac hypertrophic responses in cultured neonatal rat ventricular cardiomyocytes. TGF-beta 1 treatment resulted in upregulation of mRNA expression or promoter activities of beta-myosin heavy chain, atrial natriuretic factor, and brain natriuretic peptide, and increased myocyte protein content, cell size, and sarcomeric organization. These are all characteristic hallmarks of cardiac hypertrophy. PKC was found to be involved throughout the signaling system., and it was shown that it acts by mediating upstream TAK1 activation and leads to ATF-2 activation. PKC-dependent ATF-2 activation was shown to be involved in TGF-beta 1-induced cardiac hypertrophic responses. The PKC inhibitors, GO6976 and GF109203X, completely blocked TGF-beta 1-induced TAK1 kinase activity and subsequent downstream signaling pathways including ATF-2 phosphorylation, leading to suppression of ATF-2 transcriptional activity. This inhibitory effect was reflected in cardiac hypertrophic responses such as inhibitions of beta-MHC gene induction and ANF promoter activity. Our results suggest that PKC is involved in TGF-beta 1-induced cardiac hypertrophic responses in our cell culture system and that ATF-2 activation plays a role. (c) 2005 Elsevier Ltd. All rights reserved.