aYAP modRNA reduces cardiac inflammation and hypertrophy in a murine ischemia-reperfusion model

Life Sci Alliance. 2019 Dec 16;3(1):e201900424. doi: 10.26508/lsa.201900424. Print 2020 Jan.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / administration & dosage*
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Cardiomegaly / drug therapy*
  • Cardiomegaly / etiology*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Injections, Intramuscular
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Reperfusion Injury / complications*
  • Myocarditis / drug therapy*
  • Myocarditis / etiology*
  • Myocardium / immunology
  • Myocytes, Cardiac / metabolism
  • Neutrophil Infiltration / drug effects
  • RNA Editing
  • RNA, Messenger / administration & dosage*
  • RNA, Messenger / genetics
  • Transcription Factors / administration & dosage*
  • Transcription Factors / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • RNA, Messenger
  • Transcription Factors
  • YAP1 protein, human