Abstract 21106: The Matrikine Proline-Glycine-Proline is Locally Generated Following Acute Arterial Vascular Injury

Abstract

Introduction: Neointimal formation following vascular injury remains a clinically significant obstacle. Endovascular procedures, including percutaneous coronary intervention, disrupt the endothelium leading to inflammation and cellular proliferation within the vessel wall. Extracellular matrix (ECM) degradation by matrix metalloproteases (MMPs) has increasingly been understood to generate bioactive chemokines (i.e. matrikines) capable of causing cellular activation. Despite this knowledge, the contribution of matrikine signaling to vascular injury remains poorly understood. Hypothesis: We examined the hypothesis that the pro-inflammatory matrikines Proline-Glycine-Proline (PGP) and acetylated-PGP (AcPGP) are generated following acute arterial vascular injury. Methods: 20 male, c57bl/6 mice underwent unilateral carotid ligation of the left common carotid artery. Suture was passed, but not tied, under the contralateral carotid artery to serve as a sham procedure. Mice were sacrificed at Days 0, 1, 3 and 14 (n = 5 mice per day). Carotids and serum were harvested and processed for biochemical analysis. PGP and AcPGP were measured using liquid chromatography-tandem mass spectrometry, while total and pro-MMP9 was measured by ELISA. Results: Sham arteries had no significant induction of total or pro-MMP9 at any time. In contrast, ligated arteries showed a robust induction of both total and pro-MMP9 by Day 1 that was sustained through Day 14 (P < 0.0001 compared to mean sham arteries at all days). Importantly, PGP concentrations from ligated arteries showed a significant and sustained increase compared to Sham arteries by Day 3 (mean 150 vs 20 pg/mg carotid, P < 0.0001), while no difference was observed in AcPGP concentrations. Serum PGP and AcPGP concentrations remained low and unchanged throughout the 14-day experiment (mean ~100 and 20 pg/mL respectively). Conclusions: The current results identify PGP as a novel matrikine associated with acute vascular injury. AcPGP has previously been shown to activate endothelial cells to increase permeability and endothelin-1 synthesis via CXC Chemokine Receptor 2 (CXCR2). These results implicate PGP, a similar CXCR2 ligand, as a potentially novel mediator of inflammation following vascular injury.