Key result
Loss of the P2Y4 nucleotide receptor in mice resulted in smaller infarcts, reduced neutrophil infiltration, and decreased fibrosis following left descending artery ligation.
Why the study?
Does genetic deletion of the P2Y4 nucleotide receptor reduce infarct size and inflammation in a mouse model of myocardial infarction?
Does genetic deletion of the P2Y4 nucleotide receptor reduce infarct size and inflammation in a mouse model of myocardial infarction?
Loss of the P2Y4 nucleotide receptor protects against myocardial infarction and cardiac inflammation in mice, potentially through endothelin-1 downregulation, offering a novel therapeutic target for cardiac ischemia.
P2Y4 loss may attenuate murine post-MI injury; leaves open whether receptor targeting merits human translation.
Nucleotides are released in the heart under pathological conditions, but little is known about their contribution to cardiac inflammation. The present study defines the P2Y4 nucleotide receptor, expressed on cardiac microvascular endothelial cells and involved in postnatal heart development, as an important regulator of the inflammatory response to cardiac ischemia. P2Y4-null mice displayed smaller infarcts in the left descending artery ligation model, as well as reduced neutrophil infiltration and fibrosis. Gene profiling identified inter alia endothelin-1 (ET-1) as one of the target genes of P2Y4 in ischemic heart. The reduced level of ET-1 was correlated with reduction of microvascular hyperpermeability, neutrophil infiltration, and endothelial adhesion molecule expression, and it could be explained by the decreased number of endothelial cells in P2Y4-null mice. Expression analysis of metalloproteinases and their tissue inhibitors in ischemic heart revealed reduced expression of matrix metalloproteinase (MMP)-9, reported to be potentially regulated by ET-1, and MMP-8, considered as neutrophil collagenase, as well as reduction of tissue inhibitor of MMP-1 and tissue inhibitor of MMP-4 in P2Y4-null mice. Reduction of cardiac permeability and neutrophil infiltration was also observed in P2Y4-null mice in LPS-induced inflammation model. Protection against infarction resulting from loss of P2Y4 brings new therapeutic perspectives for cardiac ischemia and remodeling.
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Horckmans et al. (2015) studied Myocardial infarction. Loss of P2Y4 nucleotide receptor vs. Wild-type mice was evaluated on Infarct size, neutrophil infiltration, and fibrosis. Loss of the P2Y4 nucleotide receptor in mice resulted in smaller infarcts, reduced neutrophil infiltration, and decreased fibrosis following left descending artery ligation.
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