Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet

Abstract

AbstractAimsThe precise molecular drivers of abdominal aortic aneurysm (AAA) remain unclear. Thymidine phosphorylase (TYMP) contributes to increased platelet activation, thrombosis, and inflammation, all of which are key factors in AAA development. Additionally, TYMP suppresses the proliferation of vascular smooth muscle cells (VSMCs), which are central to the development and progression of AAA. We hypothesize that TYMP plays a key role in AAA development.Methods and ResultsWe conducted a histological study using human AAA samples and normal abdominal aortas, revealing heightened levels of TYMP in human AAA vessel walls. To validate this observation, we utilized an Ang II perfusion-induced AAA model in wild-type C57BL/6J (WT) andTymp−/−mice, feeding them a Western diet (TD.88137) starting from 4 weeks of age. We found thatTymp−/−mice were protected from Ang II perfusion-induced AAA formation. Furthermore, by using TYMP-expressing VSMCs as well as primarily cultured VSMCs from WT andTymp−/−mice, we elucidated the essential role of TYMP in regulating MMP2 expression and activation. TYMP deficiency or inhibition by tipiracil, a selective TYMP inhibitor, led to reduced MMP2 production, release, and activation in VSMCs. Additionally, TYMP was found to promote pro-inflammatory cytokine expression systemically, and its absence attenuates TNF-α-stimulated activation of MMP2 and AKT. By co-culturing VSMCs and platelets, we observed that TYMP-deficient platelets had a reduced inhibitory effect on VSMC proliferation compared to WT platelets. Moreover, TYMP appeared to enhance the expression of activated TGFβ1 in cultured VSMCs in vitro and in human AAA vessel walls in vivo. TYMP also boosted the activation of thrombospondin-1 type 1 repeat domain-enhanced TGFβ1 signaling, resulting in increased connective tissue growth factor production.ConclusionOur findings collectively demonstrated that TYMP serves as a novel regulatory force in vascular biology, exerting influence over VSMC functionality and inflammatory responses that promote the development of AAA.Translational PerspectiveThymidine phosphorylase (TYMP) is increased in the vessel walls of patients with abdominal aortic aneurysm (AAA), and TYMP deficiency in mice reduces the incidence of AAA, suggesting that TYMP plays a crucial role in AAA development. This could be attributed to TYMP’s role in enhancing systemic inflammation and thrombosis, inhibiting vascular smooth muscle cell function, increasing the activation of matrix metalloproteinase and AKT, as well as enhancing the expression of TGFβ1 and connective tissue growth factor. Tipiracil is an FDA-approved drug known to inhibit TYMP-enhanced thrombosis. Targeting TYMP with tipiracil could represent a promising new therapeutic strategy for AAA development.