Abstract 130: Thymidine Phosphorylase Enhances Abdominal Aortic Aneurysm Formation In Mice

Abstract

Abdominal aortic aneurysm (AAA) is affected by multiple factors, including vessel wall cells, extracellular matrix, genetic disorders, etc.; however, the pathophysiology of AAA remains unclear. We recently found that thymidine phosphorylase (TYMP) is a signaling protein, and an increase of TYMP inhibits the proliferation of VSMCs, the major cell population that affects AAA progression. TYMP enhances platelet activity, thrombosis, and inflammation. These data suggest that TYMP may play a role in AAA formation. By using human AAA samples, we found that TYMP expression was significantly increased in AAA vessel walls than in healthy aortas. We thus further examined the role of TYMP in AAA formation using a mouse model. WT C57BL/6J and Tymp -/- mice were fed a western diet (TD.88137), started at 4 weeks (wks) old for 8 wks, and then received implantation of Ang II mini pump, which delivers Ang II to mice at a dose of 1 μg/kg/min for 4 wks. By echography, we found that Ang II perfusion dramatically increased inner aorta diameter at the diastolic phase in WT, but not Tymp -/- mice. Mice were sacrificed 4 wks after Ang II perfusion. AAA was confirmed in 3 of the 12 WT mice, but no AAA was found in all 11 Tymp -/- mice used. The AAA was mainly formed at the suprarenal artery level. Histological examination confirmed the presence of freshly formed or fibrotic hematoma. By using TYMP overexpressing rat VSMC cell line, C2, and its control cells, PC, we found that TYMP increased MMP2 production, secretion, and activation, which was diminished by tipiracil, a selective TYMP inhibitor. Ang II did not affect extracellular MMP2 activity in both PC and C2. TYMP facilitated TNF-α induced MMP2 activation. TYMP induced constitutive AKT phosphorylation, which was further enhanced by TNF-α. TYMP increased expression of active TGFβ1. Consequently, TYMP significantly enhanced thrombospondin-1 type 1 repeat domain (TSR) stimulated TGFβ1 signaling activation and expression of CTGF, which is correlated with severe fibrotic disorders and AAA. In summary, our study, for the first time, demonstrated that TYMP, a pyrimidine salvage pathway enzyme, plays an important role in regulating vascular biology, especially, VSMC function. TYMP-mediated microenvironment changes enhance the development of AAA.