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
- adaptorové proteiny signální transdukční aplikace a dávkování genetika MeSH
- apoptóza účinky léků MeSH
- editace RNA MeSH
- infiltrace neutrofily účinky léků MeSH
- injekce intramuskulární MeSH
- kardiomegalie farmakoterapie etiologie MeSH
- kardiomyocyty metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- messenger RNA aplikace a dávkování genetika MeSH
- modely nemocí na zvířatech MeSH
- myokard imunologie MeSH
- myokarditida farmakoterapie etiologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- novorozená zvířata MeSH
- reperfuzní poškození myokardu komplikace MeSH
- signální proteiny YAP MeSH
- transkripční faktory aplikace a dávkování genetika MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- adaptorové proteiny signální transdukční MeSH
- messenger RNA MeSH
- signální proteiny YAP MeSH
- transkripční faktory MeSH
- YAP1 protein, human MeSH Prohlížeč
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.
- Klíčová slova
- Hippo-YAP pathway, TEAD1, VGLL4, acetylation, cardiac, cardiomyocyte, degradation, necrosis, proliferation,
- MeSH
- acetylace MeSH
- adaptorové proteiny signální transdukční metabolismus MeSH
- DNA vazebné proteiny metabolismus MeSH
- fosfoproteiny metabolismus MeSH
- lidé MeSH
- novorozená zvířata MeSH
- potkani Wistar MeSH
- proliferace buněk MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- proteinové domény MeSH
- proteiny buněčného cyklu MeSH
- sekvence aminokyselin MeSH
- signální dráha Hippo MeSH
- signální proteiny YAP MeSH
- signální transdukce * MeSH
- srdce růst a vývoj MeSH
- srdeční selhání metabolismus patologie MeSH
- stabilita proteinů MeSH
- stárnutí metabolismus MeSH
- transkripční faktory TEA domény MeSH
- transkripční faktory chemie metabolismus MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adaptorové proteiny signální transdukční MeSH
- DNA vazebné proteiny MeSH
- fosfoproteiny MeSH
- protein-serin-threoninkinasy MeSH
- proteiny buněčného cyklu MeSH
- signální proteiny YAP MeSH
- Tead1 protein, mouse MeSH Prohlížeč
- transkripční faktory TEA domény MeSH
- transkripční faktory MeSH
- VGLL4 protein, mouse MeSH Prohlížeč
- Yap1 protein, mouse MeSH Prohlížeč
