Prolyl endopeptidase contributes to early neutrophilic inflammation in acute myocardial transplant rejection
Gregory A. Payne, Nirmal S. Sharma, Charitharth V. Lal, Chunyan Song, Lingling Guo, Camilla Margaroli, Liliana Viera, Siva Kumar, Jindong Li, Dongqi Xing, Melanie Bosley, Xin Xu, J. Michael Wells, James F. George, Jose Tallaj, Massoud Leesar, J. Edwin Blalock, Amit Gaggar
Gregory A. Payne, Nirmal S. Sharma, Charitharth V. Lal, Chunyan Song, Lingling Guo, Camilla Margaroli, Liliana Viera, Siva Kumar, Jindong Li, Dongqi Xing, Melanie Bosley, Xin Xu, J. Michael Wells, James F. George, Jose Tallaj, Massoud Leesar, J. Edwin Blalock, Amit Gaggar
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Research Article Cardiology Transplantation

Prolyl endopeptidase contributes to early neutrophilic inflammation in acute myocardial transplant rejection

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.

Authors

Gregory A. Payne, Nirmal S. Sharma, Charitharth V. Lal, Chunyan Song, Lingling Guo, Camilla Margaroli, Liliana Viera, Siva Kumar, Jindong Li, Dongqi Xing, Melanie Bosley, Xin Xu, J. Michael Wells, James F. George, Jose Tallaj, Massoud Leesar, J. Edwin Blalock, Amit Gaggar

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Figure 2

PE inhibition attenuates allograft inflammatory response.

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PE inhibition attenuates allograft inflammatory response. Allograft mice...
Allograft mice were treated with ZPP (10 mg/kg i.p.) or a 2% DMSO vehicle control. (A–F) illustrates representative images of H&E and IHC staining. Compared with controls (A–C), ZPP reduced allograft inflammatory cell invasion (D and E) and MPO expression (F). Although total allograft PE did not change (G) (n = 5 animals/group), ZPP administration significantly reduced serum PE activity (H) (n = 5 DMSO and n = 6 ZPP). Importantly, ZPP significantly reduced allograft PGP (I) (n = 5 DMSO and n = 6 ZPP) and ET-1 (J) (n = 5 animals/group). This observation was associated with reduced intragraft neutrophil invasion (K) (n = 5 animals/group). In contrast, concentrations of the antifibrotic peptide AcSDKP were not altered by the administration of ZPP (L) (n = 5 DMSO and n = 6 ZPP animals/group). Importantly, ZPP attenuated the expression of allograft IFN-γ and associated leukocyte chemoattractants CXCL10 and RANTES (M–O) (n = 5 DMSO and n = 7 ZPP). Results presented as mean ± SE. Student’s unpaired t test was used for each comparison. PE, prolyl endopeptidase; PGP, proline-glycine-proline; ET-1, endothelin-1; ZPP, Z-Pro-Prolinal; MPO, myeloperoxidase; AcSDKP, acetyl-N-Ser-Asp-Lys-Pro.