PhD Scientific Days 2023

Molecular Sciences - Posters L

Role of tyrosine-kinases in the angiotensin II-induced gene expressional changes in vascular smooth muscle cells

Text of the abstract

Type 1 angiotensin II receptor (AT1R) is a member of G protein-coupled receptor family (GPCR) that initiates various intracellular signaling pathways after binding its ligand, the angiotensin II (AngII). The AT1R activation in vascular smooth muscle cells (VSMCs) results in fast vasoconstriction leading to elevation of systemic blood pressure. Moreover, AT1R also conveys numerous long-term effects, such as increasing cell proliferation or migration via AngII-induced gene expression changes. These mechanisms play important role in the development of AngII related pathological conditions, like vascular remodeling, hypertension and atherosclerosis. It is already known, that the transactivation of epidermal growth factor receptor (EGFR) and other receptor tyrosine-kinases by activated AT1R have important role in these pathologic long-term effects.
Our aim was to investigate the role of AT1R mediated activation non-receptor and receptor tyrosine-kinases in AngII-induced physiological and pathophysiological long-term effects.
In this study we used primary VSMC cultures, isolated from the aorta thoracalis of young, male Wistar rats. Cells were exposed to different tyrosine-kinase inhibitor treatments before hormonal stimulations to examine which of these enzymes are involved in AngII induced long-term effects. Our previous results revealed that genes of certain dual-specificity-phosphatases (DUSP) such as DUSP5, DUSP6 and DUSP10 show significant upregulation to AngII stimuli. The DUSP phosphatases are important regulators of mitogen activated protein kinase (MAPK) cascades. Our experiments revealed that dasatinib, a Bcr-Abl and Src kinase family inhibitor, mostly used in Philadelphia chromosome-positive chronic myeloid leukemia therapy, could effectively reduce AngII mediated upregulation of the examined DUSP isoforms. Furthermore, with Western-blot analysis, we demonstrated that dasatinib significantly reduces AngII caused p38 MAPK phosphorylation, which suggests that p38 MAPK plays a crucial role in the formation of long-term effects induced by AngII. We demonstrated that the imatinib, a selective inhibitor of Bcr-Abl kinases, was not able to achieve the similar effect as the dasatinib suggesting that Src-family tyrosine kinase(s) play an important role in AngII-induced long-term cellular responses.
Our data can provide new insight into the physiology of VSMCs in response to AngII stimulation, and may lead to the development of novel types of drugs for the treatment of cardiovascular and other diseases.
Funding: Semmelweis University STIA-OTKA (STIAOTK0001); SE 250+ Kiválósági Ösztöndíj