%0 Generic
%A Suresh Babu, Sahana
%D 2011
%F heidok:12322
%K zyxin activation , zyxin in walltension , zyxin in endothelial cells
%R 10.11588/heidok.00012322
%T Molecular mechanism of wall tension-induced zyxin activation in endothelial cells
%U https://archiv.ub.uni-heidelberg.de/volltextserver/12322/
%X Hypertension is a major predisposing factor for developing chronic endothelial dysfunction and a predominantly synthetic vascular smooth muscle cell phenotype. Therefore, the disease is one of the classical risk factors for atherosclerosis, arterial hypertrophy/hyperplasia and, consequently, cardiac hypertrophy. Despite these severe clinical consequences, surprisingly little is known about the primary signalling events leading to pressure or wall tension-induced phenotype changes of vascular cells. For the first time, the mechanisms of wall tension or stretch-induced activation of the specific mechanotransducer protein zyxin and its action as a transcription factor could be delineated in endothelial cells in vitro and in situ at the molecular level. Activation of zyxin is mediated by a hierarchical chain of events starting with the cation channel TRPC3, TRPC3-mediated or reinforced release of the autacoids ET-1 and, consecutively, ANP and, finally, the ANP receptor GC-A/cyclic GMP/ protein kinase G mediated phosphorylation of zyxin at serine-142. This phosphorylation enables zyxin to translocate to the nucleus where it affects the expression of approximately 70% of all stretch sensitive genes in endothelial and smooth muscle cells by binding to a novel stretch-sensitive promoter motif, the PyPu-box. This motif is found in all zyxin-dependent genes so far analysed. The detailed characterization of this complex pathway, specifically activated in response to mechanical overload in vascular cells, opens the possibility to interfere with early phases of pressure-/stretch-induced vascular remodelling process in vivo at several levels. Besides targeting the, quite pleiotropic, main mediators of zyxin activation, ET-1 and ANP, zyxin may be targeted directly, e.g., by use of decoyoligonucleotides that specifically prevent it from acting as a transcription factor.