Glutathione S-Transferase α4 Alleviates Hyperlipidemia- Induced Vascular Neointimal Hyperplasia in Arteriovenous Grafts Via Inhibiting Endoplasmic Reticulum Stress

Neointimal hyperplasia causes the failure of coronary artery bypass grafting (CABG). Our previous studies have found endothelial dysfunction is one candidate for triggering neointimal hyperplasia, but which factors involved in this process are unclear. Glutathione S-transferase α4 (GSTA4) play an important role in metabolize 4-hydroxynonenal (4-HNE), a highly reactive lipid peroxidation product, which causes endothelial dysfunction or death. Here, we investigated the role of GSTA4 in neointima formation after arteriovenous grafts (AVGs) with or without High-fat diet (HFD). Compared with normal diet (ND), HFD caused endothelial dysfunction and increased neointima formation, concomitantly accompanied by downregulated expression of GSTA4 at the mRNA and protein levels. In vitro, overexpression of GSTA4 attenuated 4-HNE–induced endothelial dysfunction and knockdown of GSTA4 aggravated endothelial dysfunction. Furthermore,silencing GSTA4 expression facilitates the activation of 4-HNE induced endoplasmic reticulum stress (ERS) and inhibition of ERS pathway can alleviates 4-HNE-induced endothelial dysfunction. Additionally, compared with wild-type (WT)mice, mice with knockout of endothelial-specific GSTA4 (GSTA4 EC KO) exhibited exacerbated vascular endothelial dysfunction and increased neointima formation caused by HFD.Together, these results demonstrate the critical role of GSTA4 in protecting the function of endothelial cells and alleviates hyperlipidemia-induced vascular neointimal hyperplasia in arteriovenous grafts.