Endocrine Abstracts

The angiotensin II (AngII) hormone exerts a number of biological effects through the type 1 angiotensin II receptor (AT1R). One of the main targets of AngII are vascular smooth muscle cells, their stimulation activates many signaling pathways and results in gene expression changes.

Affymetrix Gene Chip experiments were performed to analyze the effects of AngII stimulation on gene expression. For the determinations, aortic thoracic aorta from young male Wistar rats were usedto obtain primary vascular smooth muscle cells (VSMCs).In our experimental set-up more than 200 genes were upregulated in response to AngII stimulation in smooth muscle cells. In our further experiments, we investigated several genes whose transcription were significantly enhanced by AngII in primary VSMCs (DUSP5, DUSP6, DUSP10, Lmcd1, HbEGF, and endothelin). Our aim was to investigate the kinetics of the gene-expression changes, and to reveal the possible signal transduction processes which lead to the altered expression changes after AngII stimulation. The results of the quantitative PCR measurements also confirmed the increased expression of selected genes upon AngII stimulation. Transcription of most genes was largest two hours after AngII stimulation. Based on our results obtained with different inhibitors, several parallel signaling pathways, e.g. MAPK/ERK signaling may play an important role in the observed gene expression changs. We also investigated the role of epidermal growth factor receptor (EGFR) transactivation in AngII-induced gene expression changes. According to our data, EGFR transactivation does not play a significant role in the gene expression changes in response to AngII stimulation, since genetic silencing of EGFR did not significantlyabolish the AngII induced changes. In our experiments with kinase inhibitors, dasatinib, which acts primarily on the soluble tyrosine kinases ABL and Src, significantly inhibited the induced gene expression changes, suggesting that soluble tyrosine kinases may play an important role in AngII-induced long-term cellular responses. Our results suggest that not only one but parallel signal transduction pathways are responsible for the AngII induced gene expression changes and their effects may be synergistic. Our results may provide important data for understanding the molecular background of various cardiovascular diseases and may even identify novel therapeutic targets. This work was supported by the National Research, Development and Innovation Fund (NKFI K116954 and NVKP_16-1-2016-0039).