Abstract
Sterile inflammation is a key determinant of myocardial reperfusion injuries. It participates in infarct size determination in acute myocardial infarction and graft rejection following heart transplantation. We previously showed that P2Y11 exerted an immunosuppressive role in human dendritic cells, modulated cardiofibroblasts’ response to ischemia/reperfusion in vitro and delayed graft rejection in an allogeneic heterotopic heart transplantation model. We sought to investigate a possible role of P2Y11 in the cellular response of cardiomyocytes to ischemia/reperfusion. We subjected human AC16 cardiomyocytes to 5 h hypoxia/1 h reoxygenation (H/R). P2Y11R (P2Y11 receptor) selective agonist NF546 and/or antagonist NF340 were added at the onset of reoxygenation. Cellular damages were assessed by LDH release, MTT assay and intracellular ATP level; intracellular signaling pathways were explored. The role of P2Y11R in mitochondria-derived ROS production and mitochondrial respiration was investigated. In vitro H/R injuries were significantly reduced by P2Y11R stimulation at reoxygenation. This protection was suppressed with P2Y11R antagonism. P2Y11R stimulation following H2O2-induced oxidative stress reduced mitochondria-derived ROS production and damages through PKCε signaling pathway activation. Our results suggest a novel protective role of P2Y11 in cardiomyocytes against reperfusion injuries. Pharmacological post-conditioning targeting P2Y11R could therefore contribute to improve myocardial ischemia/reperfusion outcomes in acute myocardial infarction and cardiac transplantation.
Highlights
Myocardial ischemia/reperfusion (I/R) is a pathologic process responsible for myocardial injuries observed in several common clinical situations
Maximal oxygen consumption measured in the presence of the uncoupling agent FCCP, reflecting maximal mitochondrial respiratory electron transport system capacity (ETS capacity) was significantly lower in h reoxygenation (H/R) compared to normoxic CTL (10.01 ± 2.56 and 19.87 ± 2.44 pmol O2.min−1 per 106 cells respectively, p < 0.05; n = 4)
These results demonstrated that AC16 cells exhibited decreased O2 consumption in different energy states following H/R
Summary
Myocardial ischemia/reperfusion (I/R) is a pathologic process responsible for myocardial injuries observed in several common clinical situations. It is the central event in the pathophysiology of acute myocardial infarction, resulting in cardiomyocytes death, and impacts the short- and long-term outcomes in heart transplantation, including chronic rejection. EATP activates purinergic receptors (P2Rs), divided into P2X ATP-gated ion channel receptors (P2X1-7) and G protein-coupled P2Y receptors (P2Y1, 2, 4, 6, 11–14) Both subtypes play important roles in immune cell functions, e.g. neutrophil migration[7], inflammasome activation[8,9] and dendritic cells (DCs) maturation[10]. We demonstrated that P2Y11R activation, in an in vivo murine model of heterotopic heart transplantation, could delay graft rejection through an attenuation of the local immuno-inflammatory response[15], emphasizing a critical role of P2Y11 in the I/R-induced inflammatory response
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