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

Abstract

Acute myocardial infarction (MI) results in loss of cardiomyocytes and abnormal cardiac remodeling with severe inflammation and fibrosis. However, how cardiac repair can be achieved by timely resolution of inflammation and cardiac fibrosis remains incompletely understood. Our previous findings have shown that dual-specificity phosphatase 6 (DUSP6) is a regeneration repressor from zebrafish to rats. In this study, we found that intravenous administration of the DUSP6 inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) improved heart function and reduced cardiac fibrosis in MI rats. Mechanistic analysis revealed that BCI attenuated macrophage inflammation through NF-κB and p38 signaling, independent of DUSP6 inhibition, leading to the downregulation of various cytokines and chemokines. In addition, BCI suppressed differentiation-related signaling pathways and decreased bone-marrow cell differentiation into macrophages through inhibiting DUSP6. Furthermore, intramyocardial injection of poly (D, L-lactic-co-glycolic acid)-loaded BCI after MI had a notable effect on cardiac repair. In summary, BCI improves heart function and reduces abnormal cardiac remodeling by inhibiting macrophage formation and inflammation post-MI, thus providing a promising pro-drug candidate for the treatment of MI and related heart diseases. This article has an associated First Person interview with the first author of the paper.

Use of Poly Lactic-co-glycolic Acid Nano and Micro Particles in the Delivery of Drugs Modulating Different Phases of Inflammation

“…However, the BCI-loaded PLGA-NP administration effectively inhibited cardiac inflammation by decreasing macrophage activation and cytokine release in experimentally infarcted rats. Also, BCI-loaded PLGA-NPs reduced cardiomyocyte death and abnormal tissue remodeling, improving heart function in the same animals [ 130 ]. Furthermore, PLGA-NPs have been tested to improve tissue repair after MI.…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…5-methoxytryptophan reduces fibrosis by downregulating macrophages and T-cells infiltration ( Hsu et al, 2021 ). Additionally, 2-benzylidene-3-cyclohexylamino-2,3-dihydro-1H-inden-1-one, the dual-specificity phosphatase six inhibitor, improves cardiac dysfunction and fibrosis in MI rats by inhibiting macrophages formation and inflammation after MI ( Zhang et al, 2023 ). Taken together, the future studies might focus on modulating different populations and phenotypes of macrophages to improve patient prognosis and cardiac remodeling.…”

From mechanisms of heart failure to clinical heart success

“…As genomics research identifies more and more loci associated with human heart failure, resources such as the International Mouse Phenotyping Consortium can help to identify and model pathogenic mutations. Alongside zebrafish, mice and human stem cell-derived in vitro systems, articles in this issue also discuss the use of rats ( Jiang et al, 2023 ; Zhang et al, 2023 ) and pigs ( Salomon et al, 2023 ; Wolf et al, 2023 ) as valuable models with strong translational potential, expanding the array of models to investigate the causes, consequences and cures for heart failure.…”

“…DUSP6 is a protein that has already been investigated in the context of heart regeneration in zebrafish, mice and rats. In their new article, Zhang et al (2023) move their focus to the inflammatory cells that are normally activated upon cardiac injury: monocytes and macrophages. They show how pharmacological inhibition of DUSP6 prevents abnormal cardiac remodelling upon experimental myocardial infarction by suppressing macrophages and inflammation.…”