Journal
CARDIOVASCULAR RESEARCH
Volume 91, Issue 1, Pages 90-98Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvr068
Keywords
Rad GTPase; Cardiac fibrosis; CTGF; C/EBP-delta
Categories
Funding
- National Basic Research Program of China [2007CB512100, 2010CB529503]
- Natural Science Foundation of China [30871026, 30671027]
- American Heart Association [09SDG2230270, 0835237N]
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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-beta 1-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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