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-beta1-induced cardiac hypertrophic responses in cultured neonatal rat ventricular cardiomyocytes. TGF-beta1 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-beta1-induced cardiac hypertrophic responses. The PKC inhibitors, GO6976 and GF109203X, completely blocked TGF-beta1-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-beta1-induced cardiac hypertrophic responses in our cell culture system and that ATF-2 activation plays a role.

中文翻译：

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TGF-beta1通过PKC依赖性ATF-2激活诱导心脏肥大反应。

一些报道表明，TAK1-MKK3 / 6-p38MAPK信号转导轴对TGF-β相关的心脏肥大很重要。尽管如此，尚未直接证明外源性TGF-β对心脏肥大和相关信号传导机制的影响。此外，尚不清楚心脏肥大中涉及的信号传导机制（TAK1上游和p38MAPK下游）的作用。在这项研究中，我们调查了新生大鼠大鼠心室心肌细胞中TGF-β1诱导的心肌肥大反应中蛋白激酶C和激活转录因子2的潜在参与。TGF-beta1处理导致β-肌球蛋白重链，心房利钠因子和脑利钠肽的mRNA表达或启动子活性上调，并增加了肌细胞蛋白含量，细胞大小，和肌节组织。这些都是心脏肥大的特征性标志。PKC被发现参与整个信号系统，并且它通过介导上游TAK1激活并导致ATF-2激活而发挥作用。PKC依赖的ATF-2激活显示参与TGF-beta1诱导的心脏肥大反应。PKC抑制剂GO6976和GF109203X完全阻断TGF-beta1诱导的TAK1激酶活性以及随后的下游信号传导途径，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。