Dataset Information

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

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.

SUBMITTER: Chen J

PROVIDER: S-EPMC6918510 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Chen Jinmiao J Ma Qing Q King Justin S JS Sun Yan Y Xu Bing B Zhang Xiaoyu X Zohrabian Sylvia S Guo Haipeng H Cai Wenqing W Li Gavin G Bruno Ivone I Cooke John P JP Wang Chunsheng C Kontaridis Maria M Wang Da-Zhi DZ Luo Hongbo H Pu William T WT Lin Zhiqiang Z

Life science alliance 20191216 1

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 ...[more]

PMID: 31843959

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Project description:RationaleWhile thrombin is the key protease in thrombus formation, other coagulation proteases, such as fXa (factor Xa) or aPC (activated protein C), independently modulate intracellular signaling via partially distinct receptors.ObjectivesTo study the differential effects of fXa or fIIa (factor IIa) inhibition on gene expression and inflammation in myocardial ischemia-reperfusion injury.Methods and resultsMice were treated with a direct fIIa inhibitor (fIIai) or direct fXa inhibitor (fXai) at doses that induced comparable anticoagulant effects ex vivo and in vivo (tail-bleeding assay and FeCl3-induced thrombosis). Myocardial ischemia-reperfusion injury was induced via left anterior descending ligation. We determined infarct size and in vivo aPC generation, analyzed gene expression by RNA sequencing, and performed immunoblotting and ELISA. The signaling-only 3K3A-aPC variant and inhibitory antibodies that blocked all or only the anticoagulant function of aPC were used to determine the role of aPC. Doses of fIIai and fXai that induced comparable anticoagulant effects resulted in a comparable reduction in infarct size. However, unbiased gene expression analyses revealed marked differences, including pathways related to sterile inflammation and inflammasome regulation. fXai but not fIIai inhibited sterile inflammation by reducing the expression of proinflammatory cytokines (IL [interleukin]-1β, IL-6, and TNFα [tumor necrosis factor alpha]), as well as NF-κB (nuclear factor kappa B) and inflammasome activation. This anti-inflammatory effect was associated with reduced myocardial fibrosis 28 days post-myocardial ischemia-reperfusion injury. Mechanistically, in vivo aPC generation was higher with fXai than with fIIai. Inhibition of the anticoagulant and signaling properties of aPC abolished the anti-inflammatory effect associated with fXai, while inhibiting only the anticoagulant function of aPC had no effect. Combining 3K3A-aPC with fIIai reduced the inflammatory response, mimicking the fXai-associated effect.ConclusionsWe showed that specific inhibition of coagulation via direct oral anticoagulants had differential effects on gene expression and inflammation, despite comparable anticoagulant effects and infarct sizes. Targeting individual coagulation proteases induces specific cellular responses unrelated to their anticoagulant effect.

Project description:Mitochondrial inner membrane protein (Mitofilin or Mic60) is a mitochondria-shaping protein that plays a key role in maintaining mitochondrial cristae structure and remodeling. We recently showed that Mitofilin knockdown in H9c2 myoblasts induces mitochondrial structural damage resulting in mitochondrial dysfunction that is responsible for cell death via apoptosis. Here, we investigated the role of Mitofilin regulation in ischemia/reperfusion (I/R) injury and studied the relationship between Mitofilin and Cyclophilin (CypD), a key regulator of mitochondrial permeability transition pore (mPTP) opening. C57Bl6 male mice hearts were subjected to different ischemia times (15, 30, or 45 min) followed by a 2 h reperfusion period, or 45 min ischemia followed by 0, 15, 30, 60, or 120 min reperfusion to determine the impact of ischemia or reperfusion times on Mitofilin levels and its interaction with CypD. We found that the increase in myocardial infarct size and the reduction of mitochondrial calcium retention capacity were concomitant with Mitofilin reduction as a function of ischemic duration. We also found that 15 min reperfusion after 45 min ischemia was sufficient to cause a reduction of Mitofilin levels compared to sham, while 45 min ischemia alone was not enough to cause a significant decrease of Mitofilin. We revealed that the c-terminus coiled-coiled domain of Mitofilin is important for its interaction with CypD and the deletion of this identified sequence resulted in a loss of Mitofilin-CypD link, dissipation of mitochondrial membrane potential and increase in cell death. A decrease of the levels of Mitofilin was also associated with mitochondrial structural integrity damage, increased reactive oxygen species (ROS) production, and calpain activity. Our results indicate that Mitofilin physically binds to CypD in the inner mitochondrial membrane and the disruption of this interaction may play a critical role in the increase of mitochondrial dysfunction and initiation of myocytes' death after I/R injury.

Dataset Information

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

Publications

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

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