A patent review of adenosine A<sub>2B</sub>receptor antagonists (2016-present)

Francucci, Beatrice; Ben, Diego Dal; Lambertucci, Catia; Spinaci, Andrea; Volpini, Rosaria; Marucci, Gabriella; Buccioni, Michela

doi:10.1080/13543776.2022.2057222

Cited by 2 publications

(1 citation statement)

References 77 publications

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“…In line with this, systemic application of an A2bR antagonist (CS-62019) strongly attenuated cardiac remodeling after acute MI in the mouse ( 58 ) and rat ( 59 ). So far only a few A2bAR antagonists have reached clinical trials ( 60 ). Third, it might be sensible to combine the blockade of trans -signaling of IL-6, e.g., with sgp130Fc ( 37 ), with the augmentation of endogenous adenosine formation.…”

Section: Discussionmentioning

confidence: 99%

IL-6 in the infarcted heart is preferentially formed by fibroblasts and modulated by purinergic signaling

Alter¹,

Henseler²,

Owenier³

et al. 2023

Journal of Clinical Investigation

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Plasma IL-6 is elevated after myocardial infarction (MI) and is associated with increased morbidity and mortality. Which cardiac cell type preferentially contributes to IL-6 and how its production is regulated is largely unknown. Here, we studied the cellular source and purinergic regulation of IL-6 formation in a murine MI model. IL-6, measured in various cell types in post MI hearts by qPCR, RNAscope and at protein level, was preferentially formed by fibroblasts (CFs). scRNAseq in infarcted mouse and human hearts confirmed this finding. Adenosine stimulated fibroblast IL-6 formation via A2bR in a Gq-dependent manner. CFs highly expressed Adora2b, rapidly degraded extracellular ATP to AMP but lacked CD73. In mice and humans Adora2B was also mainly expressed by fibroblasts (scRNAseq). Global IL-6 formation was assessed in isolated hearts in mice lacking CD73 on T-cells (CD4CD73 -/-) a condition known to be associated with adverse cardiac remodeling. The ischemia-induced release of IL-6 was strongly attenuated in CD4CD73 -/mice, suggesting adenosine-mediated modulation.Together this demonstrates that post-MI IL-6 is mainly derived from activated CFs and is controlled by T-cell derived adenosine. Purinergic metabolic cooperation between CFs and Tcells is a novel mechanism with therapeutic potential which modulates IL6 formation by the heart.

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