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

Jinmiao Chen,Haipeng Guo,Chunsheng Wang,Bing Xu,Zhiqiang Lin,Justin S King,Xiaoyu Zhang,Yan Sun,Sylvia Zohrabian,Ivone Bruno,Maria Kontaridis,Hongbo Luo,Qing Ma,John P Cooke,Wenqing Cai,William T Pu,Da-Zhi Wang,Gavin Li

doi:10.26508/lsa.201900424

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.

Highlights

Coronary artery disease is one of the leading causes of morbidity and mortality in industrialized countries
In all of the following studies, we directly injected 50 μg activates YAP (aYAP) modRNA into the border zone of the ischemic region shortly after left anterior descending coronary artery (LAD) ligation
The same volume of vehicle was injected as a control (Veh group). 2 d after IR, hearts were collected for analysis. aYAP was successfully expressed in the myocardium, as demonstrated by qRT-PCR, Western blot, and immunohistochemistry (Fig 1B–D)

Summary

Introduction

Coronary artery disease is one of the leading causes of morbidity and mortality in industrialized countries. Early percutaneous coronary intervention strategies have improved survival in acute myocardial infarction (MI) patients (Sugiyama et al, 2015), survivors remain at risk of developing heart failure. Restoration of blood flow to the ischemic heart unavoidably causes additional injury to the myocardium (Lønborg, 2015). The causes of reperfusion injury are multifactorial, including the influx of reactive oxygen species, calcium overload, inflammation, and capillary dysfunction (Prasad et al, 2009). After percutaneous coronary intervention, increased inflammatory markers, such as the circulating neutrophil count and serum C-reactive protein level, are associated with poor prognosis (Chia et al, 2009; Reindl et al, 2017). Animal studies suggest that dysregulation of inflammatory responses after myocardial injury results in worse remodeling (Nahrendorf et al, 2007; van Amerongen et al, 2007)

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Conclusion