Expression of foetal gene Pontin is essential in protecting heart against pathological remodelling and cardiomyopathy
Cardiac remodelling is a key process in the development of heart failure. Reactivation of foetal cardiac genes is often associated with cardiac remodelling. Here we study the role of Pontin (Ruvbl1), which is highly expressed in embryonic hearts, in mediating adverse remodelling in adult mouse hearts. We observe that Pontin deficiency in cardiomyocytes leads to induced apoptosis, increased hypertrophy and fibrosis, whereas Pontin overexpression improves survival, increases proliferation and reduces the hypertrophic response. Moreover, RNAseq analysis show that genes involved in cell cycle regulation, cell proliferation and cell survival/apoptosis are differentially expressed in Pontin knockout and transgenic overexpression mice. Specifically, we detect changes in the expression of Hippo pathway components in the Pontin knockout and transgenic mice. Using a cellular model we show that Pontin induces YAP activity, YAP nuclear translocation, and transcriptional activity. Our findings identify Pontin as a modulator of adverse cardiac remodelling, possibly via regulation of the Hippo pathway. This study may lead to the development of a new approach to control cardiac remodelling by targeting Pontin. Overall design: RNA-seq profiling of total RNA from the heart tissues of transgenic mice overexpressing Pontin specifically in cardiomyocytes (Pontin cTG) and wild type littermates after 2 weeks stimulation with angiotensin (1.5 mg/kg BW/day)