CTRP13 attenuates atherosclerosis by inhibiting endothelial cell ferroptosis via activating GCH1.

C1q/TNF-related protein 13 (CTRP13) is a secreted adipokine that has been shown to play an important role in a variety of cardiovascular diseases. However, the effect of CTRP13 on ferroptosis of endothelial cells and its underlying mechanism remain unclear. In the present study, we analyzed the effects of CTRP13 on endothelial dysfunction in high-lipid-induced ApoE mice and ox-LDL-induced mouse aortic endothelial cells (MAECs). In vivo experiment: Male ApoE mice fed high fat were given C1ql3 gene overexpression adeno-associated virus. The atherosclerotic plaque size, lipid content, collagen fiber proportion and iron deposition level were measured. In vitro, CTRP13 combined with ox-LDL was used to pretreat MAECs to detect cell survival rate, lipid peroxidation, iron ion deposition and mitochondrial level. In this study, CTRP13 was found to inhibit ferroptosis of endothelial cells, demonstrated by up-regulated the expression of ferroptosis protective protein glutathione Peroxidase 4 (GPX4), and decreased the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) protein. Mechanistically, gtp cyclohydrolase 1(GCH1) silencing or tetrahydrobiopterin (BH4) inhibiting may counteract the protective effect of CTRP13 on ox-LDL-induced ferroptosis of endothelial cells, which is characterized by decreased cell activity, mitochondrial damage, increased iron ion deposition and lipid peroxidation, decreased GPX4 expression, and increased ACSL4 expression. This study demonstrated for the first time that CTRP13 can improve mitochondrial oxidative stress, inhibit ferroptosis of endothelial cells and improve endothelial cell dysfunction by activating the GCH1/BH4 signaling pathway, thereby inhibiting the progression of atherosclerosis.