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Publication : Rad GTPase inhibits cardiac fibrosis through connective tissue growth factor.

First Author  Zhang J Year  2011
Journal  Cardiovasc Res Volume  91
Issue  1 Pages  90-8
PubMed ID  21382976 Mgi Jnum  J:191632
Mgi Id  MGI:5462183 Doi  10.1093/cvr/cvr068
Citation  Zhang J, et al. (2011) Rad GTPase inhibits cardiac fibrosis through connective tissue growth factor. Cardiovasc Res 91(1):90-8
abstractText  AIMS: Our previous studies documented that Rad (Ras associated with diabetes), a member of the RGK (Rad, Gem, and Kir) family of Ras-related small G protein, is significantly decreased in human failing hearts and plays an important role in attenuating cardiac hypertrophy. The goal of this study is to identify the effect of Rad on cardiac fibrosis and the underlying mechanisms. METHODS AND RESULTS: Rad knockout (KO) mice showed more severe cardiac fibrosis compared with wild-type littermate controls as detected by Sirius Red staining. Western blot analyses demonstrated that the expression of connective tissue growth factor (CTGF), a key mediator of fibrosis, increased dramatically in Rad KO mice. Overexpression of Rad in cultured neonatal cardiomyocytes suppressed both basal and transforming growth factor-beta1-induced CTGF expression. Elevated CTGF expression was observed in cardiomyocytes when Rad was reduced by RNA interference. Moreover, cardiac fibroblasts produced greater extracellular matrix (ECM) when stimulated with conditioned medium from Rad-knockdown cardiomyocytes. ECM production was completely abolished by adding a CTGF-neutralizing antibody into the medium. CCAAT/enhancer-binding protein delta (C/EBP-delta) was demonstrated to activate CTGF in cardiomyocytes. Chromatin immunoprecipitation assay and co-immunoprecipitation further demonstrated that Rad inhibited the binding of C/EBP-delta to the CTGF promoter via direct interaction with C/EBP-delta. CONCLUSION: Our data reveal that Rad deficiency can lead to cardiac fibrosis. Rad inhibits CTGF expression through binding with C/EBP-delta, thus regulating ECM production in the heart. This study suggests a potential link between decreased Rad levels and increased cardiac fibrosis in human failing hearts.
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