title: Regulation of Connective Tissue Growth Factor and Cardiac Fibrosis by an SRF/MicroRNA-133a Axis.
abstract: Myocardial fibrosis contributes to the remodeling of heart and the loss of cardiac function leading to heart failure. SRF is a transcription factor implicated in the regulation of a large variety of genes involved in cardiac structure and function. To investigate the impact of an SRF overexpression in heart, we developed a new cardiac-specific and tamoxifen-inducible SRF overexpression mouse model by the Cre/loxP strategy. Here, we report that a high level overexpression of SRF leads to severe modifications of cardiac cytoarchitecture affecting the balance between cardiomyocytes and cardiac fibroblasts and also a profound alteration of cardiac gene expression program. The drastic development of fibrosis was characterized by intense sirius red staining and associated with an increased expression of genes encoding extracellular matrix proteins such as fibronectin, procollagen type 1α1 and type 3α1 and especially connective tissue growth factor (CTGF). Furthermore miR-133a, one of the most predominant cardiac miRNAs, is strongly downregulated when SRF is overexpressed. By comparison a low level overexpression of SRF has minor impact on these different processes. Investigation with miR-133a, antimiR-133a and AdSRF-VP16 experiments in H9c2 cardiac cells demonstrated that: 1)-miR-133a acts as a repressor of SRF and CTGF expression; 2)-a simultaneous overexpression of SRF by AdSRF-VP16 and inhibition of miR-133a by a specific antimiR increase CTGF expression; 3)-miR-133a overexpression can block the upregulation of CTGF induced by AdSRF-VP16. Taken together, these findings reveal a key role of the SRF/CTGF/miR-133a axis in the regulation of cardiac fibrosis.
authors.affiliation: Biology of Adaptation and Ageing, Institut de Biologie Paris Seine (IBPS), DHU FAST Sorbonne Universités, UPMC Université Paris 06, Paris, France; CNRS, UMR8256, Paris, France; INSERM, U1164, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Angelini
authors.affiliation: Biology of Adaptation and Ageing, Institut de Biologie Paris Seine (IBPS), DHU FAST Sorbonne Universités, UPMC Université Paris 06, Paris, France; CNRS, UMR8256, Paris, France; INSERM, U1164, Paris, France.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Biology of Adaptation and Ageing, Institut de Biologie Paris Seine (IBPS), DHU FAST Sorbonne Universités, UPMC Université Paris 06, Paris, France; CNRS, UMR8256, Paris, France; INSERM, U1164, Paris, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Mericskay
authors.affiliation: Biology of Adaptation and Ageing, Institut de Biologie Paris Seine (IBPS), DHU FAST Sorbonne Universités, UPMC Université Paris 06, Paris, France; CNRS, UMR8256, Paris, France; INSERM, U1164, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Decaux
mesh_terms: D000818:Animals; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D026362:Serum Response Factor; D055513:Connective Tissue Growth Factor