Abstract 456: YAP-TEAD1-OSM Amplification Loop Plays a Critical Role in Mediating Cardiomyocyte De-differentiation

• Published in: Circulation research 2018-08, Vol.123 (Suppl_1)
• Main Authors: Mizushima, Wataru, Ikeda, Shouhei, Zhai, Peiyong, Sadoshima, Junichi
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.123.suppl_1.456

Abstract only The Hippo pathway regulates organ size by inhibiting cell proliferation and promoting apoptosis through negative regulation of YAP, a transcription factor co-factor. Suppression of Hippo and activation of YAP promotes myocardial regeneration after myocardial infarction. However, our recent results suggest that Hippo downregulation and activation of YAP induce de-differentiation of cardiomyocytes (CMs) through activation of genes regulated by TEAD1, which in turn induces contractile dysfunction in the presence of pressure overload (PO). Since oncostatin M (OSM), a member of the interleukin-6 family of cytokines, is a mediator of CM de-differentiation, we evaluated whether OSM plays an important role in mediating CM de-differentiation in WW45 cKO mice, a mouse model of Hippo downregulation, during PO. RNA sequencing analyses showed that OSM receptors (OSMRs) are upregulated in WW45 cKO mice in response to PO. Immunoblot analyses showed that both OSM and OSMR are upregulated by PO and that their levels are further increased in WW45 cKO mice. Upregulation of OSM and OSMR was also observed in adult cardiomyocytes (ACM) isolated from WW45 cKO mice after PO. Downregulation of YAP and TEAD1 significantly decreased OSM reporter gene activity in vitro , suggesting that OSM and OSMR are downstream targets of the YAP-TEAD1 pathway in CMs. Treatment of mice with OSM increased the levels of MYH7 and ACTA2, as well as YAP and TEAD1, in ACM at baseline, indicating the existence of an amplification loop composed of YAP, TEAD1 and OSM to promote CM de-differentiation. Suppression of any component of the amplification loop inhibited CM de-differentiation and cardiac dysfunction in WW45 cKO mice in response to PO. These results indicate that the YAP-TEAD1-OSM loop plays a critical role in mediating CM de-differentiation.