Department of Cardiology, Medical University of Graz, Graz, Austria.
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
J Cell Mol Med. 2020 Aug;24(15):8732-8743. doi: 10.1111/jcmm.15504. Epub 2020 Jun 22.
Stretch and tachycardia are common triggers for cardiac remodelling in various conditions, but a comparative characterization of their role in the excitation-transcription coupling (ETC) and early regulation of gene expression and structural changes is lacking. Here, we show that stretch and tachycardia directly induced hypertrophy of neonatal rat cardiac myocytes and also of non-myocytes. Both triggers induced similar patterns of hypertrophy but had largely distinct gene expression profiles. ACTA1 served as good hypertrophy marker upon stretch, while RCAN1 was found increased in response to tachycardia in a rate-dependent fashion. Mechanistically, several calcium-handling proteins, including the sodium-calcium exchanger (NCX), contributed to ETC. Phosphorylation of the calcium/calmodulin-dependent protein kinase II (CaMKII) was elevated and occurred downstream of NCX activation upon tachycardia, but not stretch. Microarray profiling revealed that stretch and tachycardia regulated around 33% and 20% genes in a NCX-dependent manner, respectively. In conclusion, our data show that hypertrophy induction by stretch and tachycardia is associated with different gene expression profiles with a significant contribution of the NCX.
拉伸和心动过速是各种情况下心脏重构的常见触发因素，但它们在兴奋-转录偶联（ETC）和早期基因表达和结构变化调节中的作用的比较特征尚不清楚。在这里，我们表明拉伸和心动过速直接诱导了新生大鼠心肌细胞和非心肌细胞的肥大。这两个触发因素都诱导了相似的肥大模式，但基因表达谱却有很大的不同。在拉伸时，ACTA1 作为良好的肥大标志物，而 RCAN1 则发现对心动过速的反应呈速率依赖性增加。在机制上，几种钙处理蛋白，包括钠钙交换体（NCX），有助于 ETC。钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）的磷酸化在心动过速时升高，并发生在 NCX 激活的下游，但在拉伸时没有。微阵列分析显示，拉伸和心动过速分别以 NCX 依赖性方式调节约 33%和 20%的基因。总之，我们的数据表明，拉伸和心动过速诱导的肥大与不同的基因表达谱相关，其中 NCX 有重要贡献。
