The tight junction protein ZO-2 mediates proliferation of vascular smooth muscle cells via regulation of Stat1

Item Type:	Article
Title:	The tight junction protein ZO-2 mediates proliferation of vascular smooth muscle cells via regulation of Stat1
Creators Name:	Kusch, A. and Tkachuk, S. and Tkachuk, N. and Patecki, M. and Park, J.K. and Dietz, R. and Haller, H. and Dumler, I.
Abstract:	Aims: Recent evidence suggests that the zonula occludens protein 2 (ZO-2) might have additional cellular functions, beyond regulation of paracellular permeability of epithelial and endothelial cells. Deregulation of ZO-2 in response to ischemia, hypertensive stress and vascular injury implies its involvement in cardiovascular disorders, most likely via regulating the functional behavior of vascular smooth muscle cells (VSMC). However, a role of ZO-2 in VSMC biology has yet to be established. Our study was designed to understand the specific functions of ZO-2 in human VSMC. Methods: ZO-2 and Stat1 expression upon vascular injury were studied using ex vivo organ culture of coronary arteries combined with immunohistochemistry. ZO-2 silencing in human primary VSMC was achieved by means of lentiviral gene transfer. Cell proliferation was assessed by analyzing DNA synthesis and by cell counting. Stat1 expression was examined using immunoblotting, immunocytochemistry, TaqMan and FACS analysis. Functional relevance of Stat1 up-regulation was studied using a Stat1 promoter-luciferase reporter assay and intracellular microinjections of a Stat1 specific antibody. Results: ZO-2 was highly expressed in the media and neointima of dilated but not of control arteries, whereas expression of the transcription factor Stat1 was inversely regulated upon injury. Analysis of VSMC with down-regulated ZO-2 revealed increased expression of Stat1 in these cells, whereas Stat1 phosphorylation was not affected. Stat1 up-regulation in VSMC with ZO-2 silencing resulted in a coordinate activation of Stat1-specific genes and lead consequently to inhibition of cell proliferation. This effect was restored by microinjection of a Stat1 neutralizing antibody. Conclusions: Our data suggest that the tight junction protein ZO-2 is involved in regulation of VSMC growth control upon vascular injury that is mediated by the transcription factor Stat1. Our findings point to a novel function of ZO-2 in VSMC and imply ZO-2 as a novel important molecular target in pathological states of vascular remodeling in cardiovascular diseases.
Keywords:	ZO-2, Stat1, Vascular Smooth Muscle Cells, Cell Proliferation, Vascular Remodelling, Animals, Swine
Source:	Cardiovascular Research
ISSN:	0008-6363
Publisher:	Oxford University Press
Volume:	83
Number:	1
Page Range:	115-122
Date:	1 July 2009
Additional Information:	This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Cardiovascular Research following peer review. The definitive publisher-authenticated version is available online at: http://cardiovascres.oxfordjournals.org/cgi/content/full/83/1/115
Official Publication:	https://doi.org/10.1093/cvr/cvp117
PubMed:	View item in PubMed

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