T-cell death-associated gene 8 accelerates atherosclerosis by promoting vascular smooth muscle cell proliferation and migration.

Background And Aims: Atherosclerosis is a serious cardiovascular disease, featuring inflammation, abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). During atherosclerosis, inflammation may cause low pH. T-cell death-associated gene 8 (Tdag8) is a proton-sensing receptor, however, the role of Tdag8 in VSMCs remains unknown. This study aimed to investigate the potential effects of Tdag8 in VSMCs during atherosclerosis.

Methods: We examined the expression of Tdag8 in an atherosclerotic model of high-fat-diet-fed ApoE mice, while the role and mechanism of Tdag8 in phenotype transformation, proliferation and migration of VSMCs were investigated in a series of in vivo and in vitro experiments.

Results: We first found that Tdag8 expression at the mRNA and protein level was significantly increased in atherosclerotic ApoE mice. Immunofluorescence staining showed that Tdag8 was primarily distributed in PCNA-positive VSMCs and the phenotype of VSMCs switching from contractile phenotype to synthetic phenotype. Additionally, the protein level of Tdag8 was upregulated in FBS-treated VSMCs. VSMCs proliferation and migration were inhibited by Tdag8 silencing and increased by Tdag8 overexpression. Further mechanistic studies showed that cAMP level was increased in Tdag8-overexpressing VSMCs and ApoE mice. However, the PKA inhibitor H-89 reversed Tdag8-induced VSMC proliferation and migration.

Conclusions: The results demonstrate that Tdag8 mediated phenotype transformation, proliferation and migration of VSMCs via the cAMP/PKA signaling pathway, thus partially contributing to atherosclerosis.