Subacute treatment of carprofen facilitate splenocardiac resolution deficit in cardiac injury

Inflammation-limiting nonsteroidal pain relievers magnify myocardial infarction (MI) incidences and increase re-admission events in heart failure (HF) patients.However, the molecular and cellu- lar mechanism of this provocative adverse effect is unclear. Our goal was to determine whether carprofen (CAP) impedes splenic leukocyte-directed acute inflammation-resolving response in cardiac injury. After subacute CAP treatment, mice were subjected to permanent coronary lig- ation maintaining MI- and naïve-controls. Spleen and left ventricle (LV) leukocytes were quanti- tated using flow cytometry pre- and 24 h post-MI. The inflammation resolution mediators were quantified using mass spectrometry while splenocardiac apoptosis and leukocyte phagocytosis were measured by immunofluorescence and ImageStream, respectively. SubacuteCAPtreatment promoted strain and cardiac dysfunction beforeMI and coronary occlusion showed signs of acute HFinCAPand MI-controls. SubacuteCAP-injectedmice had pre-activated splenic neutrophils, an over activated “don’t eat me” signal (CD47) with reduced totalM흓s (F4/80+) and reparativeM흓s (F4/80/Ly6Clo/CD206) compared with control in LVand spleen. Post-MI, CAP pre-activated neu- trophils (Ly6G+) were intensified and reduced reparative neutrophils (Ly6G+/CD206+)andM흓s (F4/80/Ly6Clo) in LV was indicative of non-resolving inflammation compared with MI-control. SubacuteCAPtreatment deferredneutrophilphagocytosis functions in the spleenand LVandwas more evident post-MI comparedwithMI-control. CAP pre-activated splenic neutrophils that tai- lored theM흓phagocytosis thereby increased splenocardiac leukocyte death. CAP over amplified COX-1 and COX-2 compared with MI-control and failed to limit prostaglandins and thrombox- ane in post-MI setting. Further, CAP reduced cardiac-protective epoxyeicosatrienoic acids and over amplified pyrogenic inflammatory cytokines and reduced reparative cytokines, thereby non- resolving inflammation.