GALNT3 protects against vascular calcification by reducing oxidative stress and apoptosis of smooth muscle cells.

Abstract

Vascular calcification (VC) is the pathological deposition of calcium and phosphate minerals in blood vessels, which is a common complication of atherosclerosis. Polypeptide N-acetylgalactosamine transferase 3 (GALNT3) initiates O-glycosylation of proteins through addition of GalNAc to specific serine or threonine residues. Our previous studies revealed the potent role of GALNT3 in atherosclerosis, whereas the precise mechanisms remain obscure. This study investigated the regulatory effect and mechanism of GALNT3 on VC. Firstly, GALNT3 was overexpressed and knocked down by adenovirus in high-phosphate induced calcified HASMCs and overexpressed by adeno-associated virus in vitamin D3-induced arterial calcification mice. We showed that the calcium deposition and mRNA expression of osteogenic markers MSX2, ALPL, and Runx2 were all significantly reduced with GALNT3 overexpression. Moreover, overexpression of GALNT3 significantly down-regulated the expression of the oxidative stress markers Nox2 and Nox4, up-regulated total antioxidant capacity, decreased the expression of pro-inflammatory factors IL-1β, TNF-α and IL-8, matrix metalloproteinases MMP2 and MMP9, as well as reduced the apoptosis of cells in phosphate induced HASMCs. Furthermore, Vicia Villosa Lectin (VVL) pull down and TNFR1 immunoprecipitation assays showed that GALNT3 overexpression increased O-GalNAcylation of TNFR1 and blocked the activation of NF-κB signaling pathway. In addition, GALNT3 attenuates vitamin D3-induced aortic calcification in mice by alleviating oxidative stress and apoptosis of smooth muscle cells. In conclusion, this study indicates that GALNT3 protects against VC by reducing oxidative stress, vascular inflammation, and apoptosis of smooth muscle cells through the TNFR1/NF-κB signaling pathway. Thus, GALNT3 may be a potential therapeutic target for VC.

• Authors: Yi-Kai Wang, Shi-Jie Li, Lu-Lu Zhou, Duan Li, Li-Wei Guo
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 939 Pg. 175447 (Jan 15 2023) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 36473594 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Receptors, Tumor Necrosis Factor, Type I
• NF-kappa B
• Calcium
• Phosphates

Topics

• Mice
• Animals
• Receptors, Tumor Necrosis Factor, Type I (genetics)
• NF-kappa B (metabolism)
• Calcium (metabolism)
• Vascular Calcification (metabolism)
• Myocytes, Smooth Muscle (metabolism)
• Oxidative Stress
• Apoptosis
• Phosphates (metabolism)
• Atherosclerosis (pathology)
• Cells, Cultured