Abstract
Activation of the type I angiotensin receptor (AT1-R) in vascular smooth muscle cells (VSMCs) plays a crucial role in the regulation of blood pressure; however, it is also responsible for the development of pathological conditions such as vascular remodeling, hypertension and atherosclerosis. Stimulation of the VSMC by angiotensin II (AngII) promotes a broad variety of biological effects, including gene expression changes. In this paper, we have taken an integrated approach in which an analysis of AngII-induced gene expression changes has been combined with the use of small-molecule inhibitors and lentiviral-based gene silencing, to characterize the mechanism of signal transduction in response to AngII stimulation in primary rat VSMCs. We carried out Affymetrix GeneChip experiments to analyze the effects of AngII stimulation on gene expression; several genes, including DUSP5, DUSP6, and DUSP10, were identified as upregulated genes in response to stimulation. Since various dual-specificity MAPK phosphatase (DUSP) enzymes are important in the regulation of mitogen-activated protein kinase (MAPK) signaling pathways, these genes have been selected for further analysis. We investigated the kinetics of gene-expression changes and the possible signal transduction processes that lead to altered expression changes after AngII stimulation. Our data shows that the upregulated genes can be stimulated through multiple and synergistic signal transduction pathways. We have also found in our gene-silencing experiments that epidermal growth factor receptor (EGFR) transactivation is not critical in the AngII-induced expression changes of the investigated genes. Our data can help us understand the details of AngII-induced long-term effects and the pathophysiology of AT1-R. Moreover, it can help to develop potential interventions for those symptoms that are induced by the over-functioning of this receptor, such as vascular remodeling, cardiac hypertrophy or atherosclerosis.
Highlights
Angiotensin II (AngII) is an octapeptide hormone that is the main effector of the reninangiotensin system, and participates in the physiological and pathological mechanisms leading to cardiovascular diseases
Since EGF-receptor transactivation plays an important role in the angiotensin II (AngII)-induced cell responses in vascular smooth muscle cells (VSMCs), we investigated the effect of direct EGF-receptor stimulation on dual-specificity mitogen-activated protein kinase (MAPK) phosphatase (DUSP)
Since the activity and expression of various DUSP isoforms are dependent on MAPKs [18], we aimed to evaluate the role of MAPKs in AngII-induced DUSP expression changes
Summary
Angiotensin II (AngII) is an octapeptide hormone that is the main effector of the reninangiotensin system, and participates in the physiological and pathological mechanisms leading to cardiovascular diseases. AngII most importantly acts through the type 1 angiotensin II receptor (AT1 -R), a versatile G protein-coupled receptor (GPCR) that is able to promote a broad variety of biological effects, both short-term and long-term [1,2]. Gq/11 activation in VSMCs, resulting in second messenger generation (Ca2+ signal via inositol trisphosphate and diacylglycerol) upon agonist binding. This “classical” Gq/11 protein-mediated signaling mechanism is responsible for the majority of AngII-evoked physiological responses in target cells, but AT1 -R is able to activate Gi/o or G12/13 proteins as well [3,4]. There are other AT1 -R-mediated signaling mechanisms that are
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