Diverse forms of cardiomyopathies result in cardiac compensatory remodeling that may progress to ventricular dilation and heart failure. This remodeling is characterized by an increase in the size of cardiomyocytes associated with elevated rates of RNA synthesis and the activation of foetal cardiac genes. It has been shown that Bcl11b, a transcription factor, interacts with the RNApolymeraseII regulatory complex pTefb and exert an inhibitory action on it.

To determine the role of Bcl11b in regulating transcription during cardiac homeostasis and remodeling.

We generated Bcl11b cardiac-specific, tamoxifen inducible, KO mice and analyzed the phenotype at the functional, morphological and molecular levels. We also inactivated Bcl11b in isolated cardiac cells using Cre expressing adenoviruses.

We observed a compromised contractile function in the Bcl11b KO mice by echocardiography, two and six months post-inactivation, evidenced by a 10% decrease in ejection and shortening fractions. At the morphological level, Sirius red staining showed fibrotic regions in mutants’ heart. At the molecular level, hypertrophy markers such as ANF and BNP were upregulated as well as collagen genes. We also observed an increased phosphorylation of SMAD2, which is part of the TGFβ signaling that promotes fibrosis, in mutant mice. In vitro, Bcl11b KO isolated cardiomyocytes showed a downregulation of cardiac transcription factors GATA4, Mef2c and Nkx2.5, with no variations in collagen genes (Fig. 1).

Our results suggest that Bcl11b plays a crucial role in cardiac remodeling and the onset of fibrosis. Future experiments will allow us to decipher how Bcl11b is implicated in the molecular mechanisms that govern the onset of pathological cardiac remodeling. In the long term this study could pave the way for potential pharmacological approaches aiming to control and modulate the extent of cardiac hypertrophy and restore myocardial phenotype and function.