P6302GALNT4 enhances monocyte adherence and chemotaxis by regulating PSGL1 O-glycosylation in patients with acute coronary syndrome

Abstract

Abstract Background GalNAc-T4 (GALNT4), a member of N-acetylgalactosaminyltransferases family, which transfers GalNAc to Serine and Threonine residues in the initial step of O-linked protein glycosylation. Genome wide association studies (GWAS) have predicted that GALNT4 gene play a causal role in the susceptibility to cardiovascular diseases, whereas the precise mechanisms of it in acute coronary disease (ACS) is unknown. Purpose In this study, we sought to determine the role of GALNT4 in regulating monocytes with ACS and the underlying mechanisms. Methods and results The expression of GALNT4 mRNA was significantly elevated in patience with STEMI (n=50) compare with stable coronary heart disease (SCHD) (n=50) and controls (n=50) (Clinicaltrial.gov: NCT 03335514). Moreover, GALNT4 siRNA knockdown suppressed monocytes adherence under static and flow condition with P-selectin stimulation, as well as chemotaxis triggered by monocyte chemotactic protein-1 (MCP-1). In contrast, adenovirus mediated GALNT4 overexpression enhanced monocytes adherence and chemotaxis. Furthermore, vicia villosa lectin (VVL) pull down and PSGL1 immunoprecipitation assays showed that GALNT4 overexpression increased VVL binding to PSGL-1 and P-selectin induce phosphorylation of Akt and mTOR. Conversely, knockdown of GALNT4 decreased VVL binding and attenuated the activity of Akt /mTOR. Additionally, mTOR inhibitor rapamycin blocked these effects of GALNT4 overexpression on monocytes. Conclusion Expression of GALNT4 was increased in patience with ACS, GALNT4 overexpression enhances the adherence and chemotaxis of monocytes via modifying O-glycosylation of PSGL-1 and activity Akt/mTOR pathway. These findings suggest that GALNT4 may be a potential therapeutic target for ACS. Acknowledgement/Funding The National Natural Science Foundation of China (No. 81100220 and No. 81770340)