Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy

• DOI: 10.1172/jci.insight.93343
• Publication Date: 2017-09-06T21:27:40Z
• Authors: Ruya Liu; Jeongkyung Lee; Byung S. Kim; Qiongling Wang; Samuel K. Buxton; Nikhil Balasubram...; Jean J. Kim; Jianrong Dong; Aijun Zhang; Shumin Li; Anisha A. Gupte; Dale J. Hamilton; James F. Martin; George G. Rodney; Cristian Coarfa; Xander H.T. Wehrens; Vijay K. Yechoor; Mousumi Moulik
• Keywords: Phospholamban; Dilated Cardiomyopathy

Heart disease remains the leading cause of death worldwide, highlighting a pressing need to identify novel regulators cardiomyocyte (CM) function that could be therapeutically targeted. The mammalian Hippo/Tead pathway is critical in embryonic cardiac development and perinatal CM proliferation. However, requirement Tead1, transcriptional effector this pathway, adult heart unknown. Here, we show tamoxifen-inducible CM-specific Tead1 ablation led lethal acute-onset dilated cardiomyopathy, associated with impairment excitation-contraction coupling. Mechanistically, demonstrate cell-autonomous, direct activator SERCA2a SR-associated protein phosphatase 1 regulatory subunit, Inhibitor-1 (I-1). Thus, deletion decrease I-1 transcripts protein, consequent increase PP1-activity, resulting accumulation dephosphorylated phospholamban (Pln) decreased activity. Global transcriptomal analysis Tead1-deleted hearts revealed significant changes mitochondrial sarcomere-related pathways. Additional studies demonstrated there was trend for correlation between levels TEAD1 I-1, phosphorylation PLN, human nonfailing failing hearts. Furthermore, activity required maintain PLN expression induced pluripotent stem cell-derived (iPS-derived) CMs. To our knowledge, taken together, demonstrates nonredundant, role maintaining normal function.