Dusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction

Abstract

Dual-specificity phosphatase 6 (DUSP6) serves a specific and conserved function on the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). We previously identified Dusp6 as a regenerative repressor during zebrafish heart regeneration, therefore we propose to investigate the role of this repressor in mammalian cardiac repair. Utilizing a rat strain harboring Dusp6 nonsense mutation, rat neutrophil-cardiomyocyte co-culture, bone marrow transplanted rats and neutrophil-specific Dusp6 knockout mice, we find that Dusp6 deficiency improves cardiac outcomes by predominantly attenuating neutrophil-mediated myocardial damage in acute inflammatory phase after myocardial infarction. Mechanistically, Dusp6 is transcriptionally activated by p38-C/EBPβ signaling and acts as an effector for maintaining p-p38 activity by down-regulating pERK and p38-targeting phosphatases DUSP1/DUSP16. Our findings provide robust animal models and novel insights for neutrophil-mediated cardiac damage and demonstrate the potential of DUSP6 as a therapeutic target for post-MI cardiac remodeling and other relevant inflammatory diseases.

A DUSP6 inhibitor suppresses inflammatory cardiac remodeling and improves heart function after myocardial infarction

“…Macrophage infiltration is essential for initiating cardiac repair after MI. Our previous data showed that rat DUSP6 is highly enriched in neutrophils and macrophages, whereas it is hardly detectable in CMs after MI ( Zhou et al, 2022 ). After intravenous delivery of BCI daily for 7 days post-MI ( Fig.…”

“…5 C–E). DUSP6 is a classical p-ERK phosphatase and also affects p-p38 and p-JNK with lower activity ( Maillet et al, 2008 ; Zhou et al, 2022 ). Western blot analyses revealed that BCI treatment decreased the LPS-induced p-p38 proteins that are known to mediate inflammation, but had no effects on the levels of p-ERK and p-JNK ( Fig.…”

“…MI causes CM loss and structural remodeling, as well as LV dysfunction and dilation, eventually leading to heart failure ( Alonso-Herranz et al, 2020 ). Previous studies have shown that deletion or inhibition of DUSP6 promotes heart regeneration in zebrafish ( Han et al, 2014 ), mice ( Maillet et al, 2008 ; Missinato et al, 2018 ) and rats ( Zhou et al, 2022 ). Here, we reported the beneficial effects of DUSP6 allosteric inhibitor BCI, by improving cardiac function and ameliorating cardiac inflammation and fibrosis at least partly through attenuating p38–NF-κB signaling, and local delivery of a single dose of PLGA-encapsulated BCI had notable effects on cardiac repair post-MI.…”

“…Neonatal (postnatal day 3) Sprague-Dawley (SD) rats, and adult mice and rats used in this work were purchased from Vital River Laboratory Animal Technology Co., Ltd (Beijing, China). Dusp6 knockout rats were constructed in our laboratory as previously reported ( Zhou et al, 2022 ). All procedures involving experimental animals were performed according to protocols approved by the Institutional Animal Care and Use Committee at Peking University, Beijing, China.…”

“…DUSP6 functions as an oncogene or tumor suppressor, depending on the type of cancer ( Ahmad et al, 2018 ; Low and Zhang, 2016 ), and it also plays a vital role in embryogenesis ( Li et al, 2007 ), as well as heart development and regeneration ( Han et al, 2014 ; Maillet et al, 2008 ; Zhang et al, 2021 ). In addition, DUSP6 has been reported to work as an important mediator of inflammatory processes in T-cell immunity and differentiation ( Hsu et al, 2018 ; Li et al, 2015 ), neutrophils ( Zhou et al, 2022 ) and macrophage-mediated inflammation ( Cheng et al, 2018 ). ( E )-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1 H -inden-1-one (BCI), a small-molecule inhibitor of DUSP6 that was first isolated through chemical screening in zebrafish, upregulates fibroblast growth factor-targeted gene expression ( Molina et al, 2009 ).…”