Myocardial recovery from ischemia-reperfusion (IR) is shaped by the interaction of many signaling pathways and tissue repair processes, including the innate immune response. We and others previously showed that sustained expression of the transcriptional co-activator yes-associated protein (YAP) improves survival and myocardial outcome after myocardial infarction. Here, we asked whether transient YAP expression would improve myocardial outcome after IR injury. After IR, we transiently activated YAP in the myocardium with modified mRNA encoding a constitutively active form of YAP (aYAP modRNA). Histological studies 2 d after IR showed that aYAP modRNA reduced cardiomyocyte (CM) necrosis and neutrophil infiltration. 4 wk after IR, aYAP modRNA-treated mice had better heart function as well as reduced scar size and hypertrophic remodeling. In cultured neonatal and adult CMs, YAP attenuated H2O2- or LPS-induced CM necrosis. TLR signaling pathway components important for innate immune responses were suppressed by YAP/TEAD1. In summary, our findings demonstrate that aYAP modRNA treatment reduces CM necrosis, cardiac inflammation, and hypertrophic remodeling after IR stress.

• MeSH
• Adaptor Proteins, Signal Transducing administration & dosage   genetics   MeSH
• Apoptosis drug effects   MeSH
• RNA Editing MeSH
• Neutrophil Infiltration drug effects   MeSH
• Injections, Intramuscular MeSH
• Cardiomegaly drug therapy   etiology   MeSH
• Myocytes, Cardiac metabolism   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• RNA, Messenger administration & dosage   genetics   MeSH
• Disease Models, Animal MeSH
• Myocardium immunology   MeSH
• Myocarditis drug therapy   etiology   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Animals, Newborn MeSH
• Myocardial Reperfusion Injury complications   MeSH
• Transcription Factors administration & dosage   genetics   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Binding of the transcriptional co-activator YAP with the transcription factor TEAD stimulates growth of the heart and other organs. YAP overexpression potently stimulates fetal cardiomyocyte (CM) proliferation, but YAP's mitogenic potency declines postnatally. While investigating factors that limit YAP's postnatal mitogenic activity, we found that the CM-enriched TEAD1 binding protein VGLL4 inhibits CM proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for degradation. Importantly, VGLL4 acetylation at lysine 225 negatively regulated its binding to TEAD1. This developmentally regulated acetylation event critically governs postnatal heart growth, since overexpression of an acetylation-refractory VGLL4 mutant enhanced TEAD1 degradation, limited neonatal CM proliferation, and caused CM necrosis. Our study defines an acetylation-mediated, VGLL4-dependent switch that regulates TEAD stability and YAP-TEAD activity. These insights may improve targeted modulation of TEAD-YAP activity in applications from cardiac regeneration to cancer.

• MeSH
• Acetylation MeSH
• Adaptor Proteins, Signal Transducing metabolism   MeSH
• DNA-Binding Proteins metabolism   MeSH
• Phosphoproteins metabolism   MeSH
• Humans MeSH
• Animals, Newborn MeSH
• Rats, Wistar MeSH
• Cell Proliferation MeSH
• Protein Serine-Threonine Kinases metabolism   MeSH
• Protein Domains MeSH
• Amino Acid Sequence MeSH
• Signal Transduction * MeSH
• Heart growth & development   MeSH
• Heart Failure metabolism   pathology   MeSH
• Protein Stability MeSH
• Aging metabolism   MeSH
• Transcription Factors chemistry   metabolism   MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH