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
- 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
The fused quinazolinone derivative, RX-207, is chemically and functionally related to small molecule inhibitors of protein binding to glycosaminoglycans (SMIGs). Composed of a planar aromatic amine scaffold, it inhibits protein binding to glycosaminoglycans (GAGs). RX-207 reduced neutrophil migration in thioglycollate-induced peritonitis (37%), inhibited carrageenan-induced paw edema (32%) and cerulein-induced pancreatitis (28%), and increased animal survival in the mouse model of cecal ligation and puncture (CLP)-induced sepsis (60%). The mechanism of RX-207 action, analyzed by UV spectroscopy, confirmed that which was elucidated for chemically related anti-inflammatory SMIGs. RX-207 binding to cell surface GAGs can account for the inhibition of neutrophil recruitment via the micro-vasculature and as a consequence, the reduction of neutrophil mediated tissue damage in the animal models of inflammation and improved survival of mice in CLP-induced sepsis.
- MeSH
- antiflogistika farmakologie MeSH
- buněčná adheze účinky léků MeSH
- cékum mikrobiologie chirurgie MeSH
- chinazolinony farmakologie MeSH
- edém chemicky indukované metabolismus patologie prevence a kontrola MeSH
- glykosaminoglykany metabolismus MeSH
- infiltrace neutrofily účinky léků MeSH
- ligace MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- neutrofily účinky léků metabolismus mikrobiologie MeSH
- pankreatitida chemicky indukované metabolismus patologie prevence a kontrola MeSH
- peritonitida chemicky indukované metabolismus patologie prevence a kontrola MeSH
- punkce MeSH
- sepse metabolismus mikrobiologie patologie prevence a kontrola MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
