Subacute treatment of carprofen facilitate splenocardiac resolution deficit in cardiac injury

Abstract

Inflammation-limiting nonsteroidal pain relievers magnify myocardial infarction (MI) incidences and increase re-admission events in heart failure (HF) patients. However, the molecular and cellular 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 ligation maintaining MI- and naïve-controls. Spleen and left ventricle (LV) leukocytes were quantitated 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. Subacute CAP treatment promoted strain and cardiac dysfunction before MI and coronary occlusion showed signs of acute HF in CAP and MI-controls. Subacute CAP-injected mice had pre-activated splenic neutrophils, an over activated "don't eat me" signal (CD47) with reduced total Mϕs (F4/80 ) and reparative Mϕs (F4/80/Ly6C /CD206) compared with control in LV and spleen. Post-MI, CAP pre-activated neutrophils (Ly6G ) were intensified and reduced reparative neutrophils (Ly6G /CD206 ) and Mϕs (F4/80/Ly6C ) in LV was indicative of non-resolving inflammation compared with MI-control. Subacute CAP treatment deferred neutrophil phagocytosis functions in the spleen and LV and was more evident post-MI compared with MI-control. CAP pre-activated splenic neutrophils that tailored the Mϕ phagocytosis thereby increased splenocardiac leukocyte death. CAP over amplified COX-1 and COX-2 compared with MI-control and failed to limit prostaglandins and thromboxane 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.

Race‐based and sex‐based differences in bioactive lipid mediators after myocardial infarction

“…aspirin), the magnitude of infarction (minor, major, or massive), or ageing. We did not have data on diet or over‐the‐counter medications and recognize that these factors need to be considered in interpreting levels of lipid mediators in plasma of the individual patient . The influence of SES on CV disease is widely recognized.…”

“…We did not have data on diet or over-the-counter medications and recognize that these factors need to be considered in interpreting levels of lipid mediators in plasma of the individual patient. 37,[46][47][48] The influence of SES on CV disease is widely recognized. Although we collected information on education, income, and health insurance, we could not stratify by SES due to the small sample size.…”

Lack of resolution sensor drives age-related cardiometabolic and cardiorenal defects and impedes inflammation-resolution in heart failure

“…Single mononuclear cells were isolated from the spleen and left ventricle (LV) of wild-type (WT) and FPR2 −/− mice and analyzed by flow cytometry as reported previously (FACs strategy Supplementary Figure 10) [21,22].…”

Pretreatment of carprofen impaired initiation of inflammatory- and overlapping resolution response and promoted cardiorenal syndrome in heart failure

“…The lungs, LV, spleen, plasma, and kidneys were harvested and weighed, and the tibia was collected for the standardization of weights. The samples were kept in 10% zinc formalin for immunohistochemistry or flash frozen for molecular analysis (Halade et al, 2018a, Halade et al, 2018b, Lopez et al, 2015, Zamilpa et al, 2013.…”

“…The COX activity assay kit (Cayman Chemical, 760151) was used according to the manufacturer's instructions to determine COX-2 activity in the kidney tissue (Halade et al, 2018b).…”