@article{10.1172/jci.insight.139687, author = {Gregory A. Payne AND Nirmal S. Sharma AND Charitharth V. Lal AND Chunyan Song AND Lingling Guo AND Camilla Margaroli AND Liliana Viera AND Siva Kumar AND Jindong Li AND Dongqi Xing AND Melanie Bosley AND Xin Xu AND J. Michael Wells AND James F. George AND Jose Tallaj AND Massoud Leesar AND J. Edwin Blalock AND Amit Gaggar}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Prolyl endopeptidase contributes to early neutrophilic inflammation in acute myocardial transplant rejection}, year = {2021}, month = {3}, volume = {6}, url = {https://insight.jci.org/articles/view/139687}, abstract = {Altered inflammation and tissue remodeling are cardinal features of cardiovascular disease and cardiac transplant rejection. Neutrophils have increasingly been understood to play a critical role in acute rejection and early allograft failure; however, discrete mechanisms that drive this damage remain poorly understood. Herein, we demonstrate that early acute cardiac rejection increases allograft prolyl endopeptidase (PE) in association with de novo production of the neutrophil proinflammatory matrikine proline-glycine-proline (PGP). In a heterotopic murine heart transplant model, PGP production and PE activity were associated with early neutrophil allograft invasion and allograft failure. Pharmacologic inhibition of PE with Z-Pro-prolinal reduced PGP, attenuated early neutrophil graft invasion, and reduced proinflammatory cytokine expression. Importantly, these changes helped preserve allograft rejection-free survival and function. Notably, within 2 independent patient cohorts, both PGP and PE activity were increased among patients with biopsy-proven rejection. The observed induction of PE and matrikine generation provide a link between neutrophilic inflammation and cardiovascular injury, represent a potential target to reduce allogenic immune responses, and uncover a mechanism of cardiovascular disease that has been previously unrecognized to our knowledge.}, number = {6}, doi = {10.1172/jci.insight.139687}, url = {https://doi.org/10.1172/jci.insight.139687}, }